Approach to milk protein allergy in infants

Case description

Baby M. is a full-term, 4-kg infant girl delivered vaginally of a 22-year-old primiparous mother after an uneventful pregnancy. At the 2-week follow-up visit, Baby M. has regained her birth weight. Her mother reports frequent episodes of regurgitation after breastfeeding, which do not distress her. Family history is significant for environmental allergies in both parents and a paternal uncle with eczema and severe asthma. At the 4-week follow-up visit, the mother reports ongoing regurgitation followed occasionally by crying. Stools have become more frequent and appear watery. The baby’s weight is 4150 g, a gain of 10 g/d since the last visit.

Sources of information

A MEDLINE search was conducted using the MeSH heading milk-hypersensitivity. English-language articles studying subjects younger than 1 year of age were selected. Additional articles were derived from review articles found with the initial search strategy, yielding a total of 36 publications. Evidence was levels I, II, and III.

Epidemiology

Cow’s milk protein allergy (CMPA) appears to be the most common MPA, with controlled challenge trials demonstrating an incidence of 2% to 5% among formulafed infants (level I evidence).1 The incidence in breastfed infants is 0.4% to 0.5% according to 2 trials (level I evidence), 2,3 but might be as high as 2.1% (level II evidence).4 Determining the incidence of allergy to milk proteins from other sources is complicated by the widespread use of bovine milk. A population-based cohort study found the incidence of soy allergy to be 0.25% (level II evidence).5 Among high-risk infants, CMPA appears to outweigh soy milk protein allergy (SMPA) by a factor of 6 to 1 (level I evidence).6 A study by Klemola et al found the incidence of SMPA to be 10% among children with CMPA.7 Interestingly, qualitative observation alone suggested a cross-reactivity as high as 30%, but only a 10% rate was observed using rigorous quantitative measures. This underscores the importance of appropriately testing diagnostic suspicions. Cross-reactivity between milk protein from ewe, goat, or buffalo and bovine milk protein has been demonstrated in vitro.8 Unfortunately, Canadian data are lacking.

Pathophysiology

Milk protein allergy can manifest via IgE-mediated and non–IgE-mediated pathways.9 An IgE-mediated allergy (also known as type I hypersensitivity reaction) occurs when antigens bind to IgE antibodies bound to mast cells. Cross-linking of 2 IgE antibodies by an antigen causes the mast cell to release histamine, a potent inflammatory mediator, resulting in an immediate allergic reaction. Non–IgE-mediated MPA is likely multifactorial and includes immune complexes of IgA or IgG antibodies bound to milk antigens (type III hypersensitivity reaction) and direct stimulation of T cells by milk protein antigens (type IV hypersensitivity reaction). The interactions result in cytokine release and increased production of antibodies that recognize the offending milk proteins, contributing to an inflammatory cascade. These more complex immune interactions result in delayed onset of clinical symptoms. While there is overlap of clinical symptoms in the 2 groups of immune reactions,9 a non–IgE-mediated allergy is certain with isolated bloodstreaked stools (level III evidence). With the other symptoms, while a distinction might be suspected it cannot be confirmed by clinical history alone (Table 110–12). Making the distinction is important, as IgE-mediated MPA is associated with a higher risk of multiple food allergies and atopic conditions such as asthma later in life (level I and II evidence).10,13

Cross-sensitization between protein sources is well established. Among infants with CMPA, 13% to 20% have allergies to beef (level II evidence).14 Restani et al demonstrated that antibodies harvested from children with CMPA recognize milk proteins from ewe, goat, and buffalo species, but not from camels (level II evidence).8 Completely different organisms produce soy and bovine proteins. Rozenfeld et al demonstrated that a monoclonal antibody specific to casein (a bovine milk protein) displayed affinity to a component of glycinin, an ingredient in soy-based formulas.15

Clinical presentation

Infants with MPA usually present with symptoms similar to allergic reactions in older individuals. These include cutaneous symptoms such as urticaria, rash, and pruritus, as well as respiratory symptoms such as wheeze and cough (level I evidence).11 These symptoms are usually indicative of IgE-mediated MPA.9

Milk protein allergy can also present with gastrointestinal and nutritional manifestations. These include gastroesophageal reflux, esophagitis, gastritis, delayed gastric emptying, enteropathy, colitis, constipation, and failure to thrive (level I to II evidence).12 These symptoms might be the cause of behaviour such as crying inconsolably and refusing feeding. The symptoms are the same among breastfed and formula-fed infants. Gastrointestinal symptoms are particularly challenging owing to their nonspecificity and wide differential diagnosis, but MPA should always be suspected. One study administered a cow's milk—free diet to 10 infants with refractory gastroesophageal reflux that had not improved with pharmacologic therapy and reported that 2 of the infants' symptoms improved (level II evidence).16 Jakobsson et al administered hydrolyzed formula to 15 infants with severe colic and demonstrated a 60% to 70% reduction in daily crying time (level II evidence),17 but caution should be used in generalizing these results to all infants with colic.

Diagnosis

Confirming the diagnosis of MPA is important owing to the discrepancy between parental description of symptoms and scientific confirmation. 7,9 Double-blind, placebo-controlled food challenge has long been regarded as the criterion standard (level I evidence),18 however, owing to the risk of substantial allergy during food challenge, an alternative test with equal efficacy is preferred. Other investigational options include skinprick testing (SPT), serum measurement of IgE antibodies to the specific allergen, and patch testing. A recent study suggests that a combination SPT and measuring IgE antibodies results in a positive predictive value of 95% for diagnosing IgE-mediated CMPA, obviating the need for the food challenge if an IgE-mediated CMPA is suspected (level I evidence).19 A similar study, however, failed to reproduce these results (level II evidence).20 Skin-prick testing and specific IgE levels are not useful for the diagnosis of non–IgE-mediated MPA,9 but patch testing shows promise.21

Laboratory investigations are not diagnostic but can support a diagnosis made on clinical grounds. A decreased albumin level is suggestive of enteropathy (level III evidence). Increased platelets, erythrocyte sedimentation rate, C-reactive protein, and fecal leukocytes are all evidence of inflammation but are nonspecific; normal values do not rule out MPA (level III evidence). Eosinophilic leukocytosis might be present in both types of MPA.20

Management

The main principle in management of MPA is to avoid allergens while maintaining a balanced, nutritious diet for infants and mothers. Although it is difficult, breastfeeding can be continued if allergens are avoided. For CMPA, a breastfeeding mother must sequentially eliminate all cow’s milk protein, then all bovine protein (milk and meat), and occasionally other protein sources such as soy (level II evidence).22,23 A similar broad restriction is recommended for other MPAs given their low incidence and association with CMPA (level III evidence). Consultation with a dietitian is essential for a mother who continues breastfeeding; particular attention must be paid to adequate calcium intake. A list of foods containing cow’s milk and soy proteins is found in Table 2.24,25

For formula-fed infants, current options include specific allergen avoidance, extensively hydrolyzed protein formulas (EHFs), and amino acid–based formulas (AAFs) (Table 3). Extensively hydrolyzed protein formulas incorporate hydrolysates of casein or whey derived from cow’s milk. Their efficacy among those with CMPA is approximately 90% (level I to II evidence),23,26–29 though their efficacy among those with other forms of MPA is less well demonstrated. These formulas do have potentially allergenic material,30 and allergic reactions have been reported.31,32 A rice-based EHF shows promise in young children,33 but is not commercially available. Amino acid–based formulas are created from constituent amino acids and have demonstrated efficacy of approximately 99% (level I evidence)28,34; they can be considered as an immediate or secondary alternative to EHFs. However, even AAFs contain potentially allergenic material, such as soy lecithin, so their use must be monitored. The taste of the formula might be an issue for compliance; as a rule of thumb, the more hydrolyzed a formula, the worse the taste.

Specific allergen avoidance, such as substituting soy-based formulas for milk-based in CMPA, is not recommended. The concomitant presence of multiple MPAs reduces the likelihood of success of milk protein substitution.7,8 Additionally, cross-sensitization of milk proteins correlates with increased intestinal permeability (level II evidence).35 Thus, allergy-induced enteropathy might increase the risk of cross-sensitization if specific allergen avoidance is pursued during the acute phase (level III evidence). If the expense of EHFs or AAFs is a concern, in order to avoid the risk of cross-sensitization, have patients avoid alternate protein sources for at least 1 month to give the intestinal mucosa time to heal, then challenge with a protein alternative (level III evidence).

Introduction of solid food can occur at the usual age barring complications such as feeding aversion. Education regarding diet restriction is essential and is best achieved with the help of a dietitian (level III evidence). 36 The importance of a dietitian referral is underscored by a study demonstrating a high rate of parental error in avoiding milk protein–laced foods at the grocery store (level II evidence).37 Parents might also worry about lactose intolerance, and they should be reassured of the extreme rarity of lactase deficiency in infants younger than 1 year of age.38

Prognosis

The timing of reintroducing milk protein is of great concern to parents. Traditionally, it was thought that MPA resolved by 1 to 2 years of age (level III evidence).9,39 Two recent studies, however, suggest a more complex answer. Carroccio et al40 found the proportions of Italian infants with CMPA who had milk tolerance at 1, 2, and 3 years after initiation of milk-free diets were 30%, 54%, and 70%, respectively. Vanto et al41 demonstrated a difference in tolerance when considering the type of CMPA among Finnish infants (level II evidence). At 2, 3, and 4 years of age, children with non–IgE-mediated CMPA had milk tolerance at rates of 64%, 92%, and 96%, respectively, while children with IgE-mediated allergy were milk tolerant at rates of 31%, 53%, and 63% (level II evidence). Furthermore, children with less reactive SPT results and fewer specific IgE antibodies were milk tolerant sooner than children with more dramatic findings. Taken together, these results suggest that cow’s milk protein can be reintroduced in trial fashion at 1 year of age in children deemed to have non–IgE-mediated allergy, while children suspected of IgE-mediated allergy should not be exposed to cow’s milk for longer time periods, with the length of time guided by allergy testing. Data regarding resolution of other types of MPA are lacking, though children with multiple food allergies are more likely to remain allergic.

When to refer

There are no published guidelines on when to refer infants with MPA to specialist care. A list of potential situations in which it is prudent to refer infants for specialized care can be found in Table 410 (level III evidence).

Case resolution

Baby M.’s bloodwork results revealed the following: platelet count 474 × 109/mL; albumin 34 g/L; and no eosinophilic leukocytosis. Stool microscopy results revealed many fecal leukocytes per high-powered field. The mother was advised to remove all bovine milk products from her diet. She returned for a followup visit 2 weeks later and reported normalization of stools and resolution of crying with regurgitation. She was advised to resume consumption of cow’s milk products. She called the office 3 days later and reported a recurrence of the looser, more frequent stools. Upon removing cow’s milk from the diet, the stool pattern improved. A diagnosis of CMPA was made. A dietitian saw mother and infant when Baby M. was 5 months of age and provided advice regarding introduction of solid foods. Cow’s milk was reintroduced at 11.5 months of age without a relapse of symptoms, and Baby M. ate cake at her first birthday party.