Milk allergy: Clinical features and diagnosis

INTRODUCTION — Cow's milk allergy (CMA) is the most common food allergy in young children but is uncommon in adults [1]. This food allergy presents with a wide range of clinical syndromes due to immunologic responses to milk proteins that can be immunoglobulin E (IgE) mediated and/or non-IgE mediated [2-4] CMA does not include other adverse reactions to milk, such as lactose intolerance, which are nonimmune mediated [5]. (See "Lactose intolerance and malabsorption: Clinical manifestations, diagnosis, and management".)

The epidemiology, pathogenesis, clinical features, and diagnosis of CMA will be presented in this topic review. Cross-reactivity of cow's milk with other mammalian milks and management of milk allergy are discussed separately. General discussions of food allergy are presented separately in appropriate topic reviews. (See "Milk allergy: Management".)

EPIDEMIOLOGY

General population — Cow's milk allergy (CMA) is the most common food allergy in young children, affecting approximately 2 percent of children under four years of age [1]. CMA is even more prevalent in infants. Two studies published in the 1990s reported a CMA prevalence of 2.2 and 2.8 percent at one year of age in general population birth cohorts [6,7], consistent with the rate found in another cohort of over 6000 newborns followed for 18 to 34 months [8]. A pan-European Euro-Prevall birth cohort study published in 2015 confirmed challenge-proven CMA in <1 percent of children up to age two years using the gold-standard diagnostic procedure for food allergies and showed differences in national incidences ranging from 1 percent (in the Netherlands and United Kingdom) to <0.3 percent (in Lithuania, Germany, and Greece) [9].

The prevalence of CMA in adults is not as well reported [10]. The rate of CMA by patient report in a multinational survey of 17,280 adults (aged 20 to 44 years) from 15 countries that questioned participants about foods that "nearly always" caused "illness" or "trouble" was 4.3 percent. However, a much lower proportion of adults have confirmed CMA, ranging from 0.1 to 0.3 percent [1,9,11,12]. Allergy persists from childhood in a subgroup of adults with CMA, but two reports suggest that the majority of adults with CMA acquired the allergy in adulthood [13,14].

In two small series, over 80 percent of adults with CMA were female [13,14]. In contrast, childhood CMA is more prevalent in boys [15].

Referral populations — Cow's milk is the third most common food, after peanut and tree nuts, responsible for food-induced anaphylaxis in pediatric and mixed-age populations (10 to 19 percent of cases) [16-18]. Milk is also the third most common food responsible for fatal or near-fatal food-induced anaphylactic reactions (8 to 15 percent of cases) [19-22]. CMA was reported in approximately 40 percent of patients seen in a university-based pediatric allergy outpatient clinic focusing on food allergies [16]. Thirty-seven percent of children with atopic dermatitis referred to a university-based dermatology clinic had clinically significant IgE-mediated food hypersensitivity; of them, 17 percent had CMA [23]. (See "Food-induced anaphylaxis" and "Fatal anaphylaxis".)

PATHOGENESIS — Acute allergic responses to milk are due to IgE directed against various allergens in milk. All milk proteins are potential allergens, and polysensitization to several proteins occurs in most patients [24].

Cow's milk contains casein (alphaS1-, alphaS2-, beta-, and kappa-caseins) and whey (alpha-lactalbumin [ALA], beta-lactoglobulin [BLG], bovine lactoferrin, bovine serum albumin [BSA], and bovine immunoglobulins) proteins that account for approximately 80 and 20 percent of total protein, respectively [24]. Most patients with cow's milk allergy (CMA) are sensitized to several milk proteins, including BLG, casein, ALA, BSA, bovine lactoferrin, and bovine immunoglobulins [24]. Casein, BLG, and ALA are the major milk allergens, and cosensitization to these three allergens is common [24-26]. However, sensitization to milk proteins present in very low concentrations, such as bovine lactoferrin, BSA, and bovine immunoglobulins, is also seen in up to half of patients with CMA [24,26,27]. Some patients are sensitized exclusively to these minor allergens. As an example, sensitization to BSA is independent of sensitization to the other milk allergens [24]. The clinical relevance of sensitization to different milk proteins is largely unknown. (See "Pathogenesis of food allergy".)

Most commercially available cow's milk contains two types of beta-casein: A1 and A2 types. Digestion of A1 type, but not of A2 type, can yield the peptide beta-casomorphin-7, which has been implicated in adverse gastrointestinal effects of milk consumption, similar to those in lactose intolerance [28]. However, we are not aware of studies showing lower allergenicity of A2 milk, and A1 and A2 differ only in a single point mutation (Pro67 to His67). In addition, most persons with milk allergy are sensitized to several major milk allergens (not only beta-casein) and have reactivity to multiple IgE antibody-binding regions in beta-casein [29]. Thus, it appears unlikely that A2 milk would be nonallergenic and tolerated in patients with CMA.

Cooking diminishes the allergenicity of whey proteins, particularly BLG [30,31], presumably by denaturation of heat-labile proteins that results in loss of conformational epitopes. This may explain why extensively heated milk (eg, milk in baked goods) is better tolerated by many patients [32]. Similarly, yogurt cultures, which ferment and acidify milk, diminish the amount of intact whey protein in milk [31] and may result in tolerance of yogurt-based dairy products by individuals with CMA exclusively sensitized to whey proteins. (See "Molecular features of food allergens".)

The pathogenesis of non-IgE-mediated milk allergy and milk allergy due to mixed IgE- and non-IgE-mediated processes is less well understood. (See "Pathogenesis of food allergy" and "Food protein-induced allergic proctocolitis of infancy" and "Clinical manifestations and diagnosis of eosinophilic esophagitis (EoE)" and "Role of allergy in atopic dermatitis (eczema)".)

CLINICAL FEATURES — Clinical findings of cow's milk allergy (CMA) frequently appear during the first few months of life, often within days or weeks after the introduction of a cow's milk-based formula into the diet, although symptoms may also occur with exclusive breastfeeding if cow's milk protein from the maternal diet is transmitted in breast milk in sufficient quantities. Patients with CMA present with a wide range of IgE- and non-IgE-mediated clinical syndromes (table 1) [2-4,33].

IgE-mediated reactions — IgE-mediated food-triggered reactions generally occur immediately, within minutes to two hours after ingestion. These reactions can present with skin, oropharyngeal, upper and lower respiratory tract, gastrointestinal tract, and/or cardiovascular signs and symptoms (table 2 and table 3). Reactions can vary from mild to life-threatening anaphylaxis. (See "Clinical manifestations of food allergy: An overview".)

Occupational and household exposures involving inhalation of cooking or processing vapors containing milk droplets may cause respiratory symptoms. Casual contact by touching can cause localized urticaria. (See "Respiratory manifestations of food allergy" and "Clinical manifestations of food allergy: An overview".)

Mixed IgE- and non-IgE-mediated reactions — The mixed reactions may have either humoral and/or cell-mediated mechanisms and may present with acute and/or chronic symptoms.

Atopic dermatitis (eczema) — Food allergy plays a pathogenic role in a subset of patients, primarily infants and children, with atopic dermatitis. Milk is the second most common allergy reported in infants and young children with moderate-to-severe atopic dermatitis (hen's egg allergy is the most common) [34-36]. The role of food allergy in atopic dermatitis is discussed in detail separately. (See "Role of allergy in atopic dermatitis (eczema)".)

Allergic eosinophilic gastrointestinal disorders — Milk is also among the major allergens identified in allergic eosinophilic esophagitis, a disorder characterized by eosinophilic inflammation of the esophagus. Patients with this disorder have symptoms suggestive of gastroesophageal reflux (GER) but are unresponsive to conventional reflux therapies. Other presenting symptoms include feeding difficulties, vomiting, abdominal pain, dysphagia, failure to thrive, weight loss, and food impaction. Patients with allergic eosinophilic gastroenteritis (eosinophilic gastroenteropathy of the stomach and intestines) may have symptoms of abdominal pain, nausea, vomiting, diarrhea, or weight loss. (See "Clinical manifestations and diagnosis of eosinophilic esophagitis (EoE)" and "Treatment of eosinophilic esophagitis (EoE)" and "Eosinophilic gastrointestinal diseases".)

Non-IgE-mediated reactions — The non-IgE-mediated reactions usually have a delayed onset beyond two hours of ingestion [37].

Food protein-induced enterocolitis syndrome — Food protein-induced enterocolitis syndrome (FPIES) is a disease that primarily occurs in infants. It can present in one of two ways. The typical presentation is that of severe vomiting and diarrhea within two to four hours after ingestion of the offending allergen, causing profound dehydration, lethargy, and sometimes shock. The acute phase can be the first manifestation of FPIES or can occur when the allergen is removed from the diet and then reintroduced. Chronic exposure to the offending allergen may present with more subtle symptoms, such as regurgitation, diarrhea, failure to thrive, and hypoalbuminemia. Cow's milk is among the major offending allergens. FPIES in children is presented in greater detail separately. (See "Food protein-induced enterocolitis syndrome (FPIES)".)

Food protein-induced proctitis/proctocolitis — Food protein-induced proctitis/proctocolitis usually presents by six months of life with bloody-streaked, mucousy, loose stools and occasionally diarrhea in breastfed or standard formula-fed infants who are otherwise well appearing. Cow's milk and soy are the major causative foods. (See "Food protein-induced allergic proctocolitis of infancy".)

Food protein-induced enteropathy — Food protein-induced enteropathy (FPE) presents with protracted diarrhea in the first nine months of life, within weeks after the introduction of the trigger food. The majority of affected infants have failure to thrive, and some present with malabsorption. It may be difficult to distinguish FPE from postenteritis syndrome, especially because FPE can develop after infectious gastroenteritis leading to secondary lactose intolerance. This presentation has become much less common due to the common practice of switching to a hypoallergenic formula shortly after symptoms develop [8,38,39].

Heiner syndrome — Heiner syndrome (food-induced pulmonary hemosiderosis) is a pulmonary disease that is caused by food hypersensitivity, primarily to milk. This disorder mainly affects infants. Symptoms include cough, recurrent fever, wheezing, nasal congestion, recurrent otitis media, hemoptysis, failure to thrive, dyspnea, colic, anorexia, vomiting, diarrhea, and hematochezia [40]. Patients have precipitating antibodies (immunoglobulin G [IgG]) to milk proteins and may also have milk-specific IgE. Radiologic evidence of pulmonary infiltrates was a universal finding in one study [40]. This disorder is discussed in greater detail separately. (See "Clinical manifestations of food allergy: An overview", section on 'Pulmonary manifestations'.)

Other — Other disorders that are common in early infancy and may be related to CMA include gastroesophageal reflux disease (GERD), infantile colic, and constipation. However, these disorders are unlikely to be isolated or sole manifestations of CMA.

●Gastroesophageal reflux disease (GERD) – GER symptoms are seen in children with some forms of CMA, such as eosinophilic esophagitis and dietary protein-induced gastroenteropathy. When GER leads to troublesome symptoms that affect daily life, it is referred to as GERD. The role of food allergens as a cause of a food protein-induced dysmotility disorder such as GERD remains controversial, but literature has suggested that food proteins, especially cow's milk protein, are a possible contributing factor to GERD [41]. Because CMA-associated GERD and non-food allergy-associated GERD are difficult to distinguish, the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN)/North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) guidelines have recognized the possible role of CMA [42]. Thus, for infants, an elimination diet is a reasonable next step after a trial of thickened feeds and avoidance of overfeeding and before medical management [41]. (See "Gastroesophageal reflux in infants" and "Food protein-induced allergic proctocolitis of infancy" and "Clinical manifestations and diagnosis of eosinophilic esophagitis (EoE)".)

●Infantile colic – The role of diet in infantile colic is still controversial, although it may be a sign of food allergy along with other signs such as GERD, bloody stools, and diarrhea. Studies have shown an improvement in colic symptoms after a change to a soy-based or hydrolyzed cow's milk-based formula or elimination of cow's milk from the diet and worsening of symptoms upon rechallenge in some infants. (See "Infantile colic: Clinical features and diagnosis", section on 'Gastrointestinal'.)

●Constipation – Along with GERD, constipation is a proposed food protein-induced dysmotility disorder [43,44]. CMA/intolerance has been suggested as a cause of constipation in infants and children, especially in those with refractory chronic constipation, although this hypothesis is controversial. Consensus-based constipation guidelines recommend considering CMA as a possible cause of constipation in infants [45]. (See "Constipation in infants and children: Evaluation".)

NATURAL HISTORY — Tolerance is achieved by the majority of children with cow's milk allergy (CMA). Non-IgE-mediated CMA tends to resolve more quickly than IgE-mediated CMA [9]. An early report indicated that most children with IgE-mediated CMA become tolerant by three years of age [6]. However, a subsequent study suggested that IgE-mediated CMA is more persistent, with children outgrowing this allergy in later childhood and adolescence (64 percent by 12 years of age) [46]. Whether these differing results are due to population differences or a change in the natural history of milk allergy is unclear. (See "Food allergy in children: Prevalence, natural history, and monitoring for resolution".)

Several prognostic indicators for the development of tolerance to milk have been identified in patients with IgE-mediated CMA. These include lower initial level of milk-specific IgE [46], faster rate of decline of milk-specific IgE level over time [47], and absence of concomitant allergic rhinitis or asthma [46,48].

DIAGNOSIS — A general discussion of the diagnosis of food allergy is presented elsewhere. A summary of this information, with a focus on those aspects that are most relevant to the diagnosis of cow's milk allergy (CMA), is provided below. (See "History and physical examination in the patient with possible food allergy" and "Diagnostic evaluation of IgE-mediated food allergy".)

The diagnosis of CMA is based upon the history and laboratory testing, when available (diagnostic tests for non-IgE-mediated manifestations of CMA are limited) [49-52]. The gold standard for diagnosis is a clinician-supervised, double-blind, placebo-controlled oral food challenge, although an open challenge will often suffice. Measurement of cow's milk-specific IgE can aid in the diagnosis of IgE-mediated CMA and may eliminate the need for oral food challenges. (See "Oral food challenges for diagnosis and management of food allergies".)

With the exception of in vitro immunoassays for specific IgE (which are still commonly referred to as IgE radioallergosorbent tests [RAST]), other diagnostic allergy procedures, including skin testing and food challenges, should be performed by allergy specialists with training in the management of serious allergic reactions. (See "Overview of skin testing for IgE-mediated allergic disease" and "Oral food challenges for diagnosis and management of food allergies".)

IgE-mediated reactions — The history of an immediate reaction consisting of typical allergic symptoms, supported by positive tests for specific IgE antibodies, is sufficient to establish a presumptive diagnosis for suspected IgE-mediated reactions. Skin prick tests and/or in vitro tests for IgE are usually performed initially. (See "History and physical examination in the patient with possible food allergy" and "Diagnostic evaluation of IgE-mediated food allergy".)

Higher concentrations of cow's milk-specific IgE and larger skin test wheals correlate with an increased likelihood of a reaction upon ingestion, although these findings are based upon a limited number of clinical studies. Unfortunately, these values are not predictive of the nature or severity of reaction to milk.

●A cow's milk-specific IgE level of ≥15 kUA/L using the ImmunoCAP assay is 95 percent predictive of a clinical reaction to ingested milk in children ≥2 years of age [53]. A level of 5 kUA/L in children less than two years of age is similarly predictive of a reaction [54]. However, the predictive values for clinical reactivity associated with food-specific IgE levels determined by the ImmunoCAP assay should not be applied to results from other assays [55]. Component-resolved diagnosis (CRD) allows identification of IgE binding to specific proteins, such as casein, alpha-linolenic acid (ALA), or beta-lactoglobulin (BLG), which may be informative to distinguish between different phenotypes of milk allergy. Further studies are needed to determine the utility of IgE testing to individual proteins for these foods. (See "Component testing for animal-derived food allergies".)

●Similar analyses have been performed for skin testing using a commercial cow's milk extract; a wheal diameter of 8 mm in children over two years of age and 6 mm in children two years of age and under is 95 percent predictive of a clinical reaction [56,57].

When the history and testing are not conclusive, the diagnostic procedure may include elimination of the suspected food for two to eight weeks [50] followed by challenge (if the probability is higher) or reintroduction (if the probability is lower). In breastfed infants, the dietary elimination includes a maternal exclusion diet avoiding cow's milk protein and, in formula-fed infants, use of either extensively hydrolyzed or amino acid-based infant formulae (table 4 and table 5) [58]. If minimal to no improvement is noted on a milk-avoidance diet and no significant differences are noted with reintroduction (or challenge is negative), the food in question is not responsible for symptoms, the diet has not been restricted enough, or the patient may have multiple food allergies and additional foods may be considered suspicious. Oral food challenges and food allergen avoidance are covered in detail separately. (See "Oral food challenges for diagnosis and management of food allergies" and "Management of food allergy: Avoidance".)

Asthma — The diagnosis of suspected occupational asthma in adults due to IgE-mediated CMA involves skin prick testing, pulmonary function testing, and possible bronchoprovocation challenge. Occupational asthma is discussed in more detail separately. (See "Occupational asthma: Clinical features, evaluation, and diagnosis".)

Non-IgE-mediated reactions — IgE tests are expected to be negative if the symptoms do not suggest an IgE-mediated reaction, such as delayed gastrointestinal reactions and some cases of atopic dermatitis. Atopy patch testing may provide additional information in these cases. However, there are no standardized reagents, application methods, or guidelines for interpretation for atopy patch testing. Thus, this type of testing cannot be recommended outside of research settings. This method is discussed in greater detail separately, as is diagnosis of CMA in these disorders. (See "Future diagnostic tools for food allergy", section on 'Atopy patch testing' and "Clinical manifestations and diagnosis of eosinophilic esophagitis (EoE)" and "Role of allergy in atopic dermatitis (eczema)" and "Food protein-induced allergic proctocolitis of infancy" and "Future diagnostic tools for food allergy".)

Diagnostic pitfalls — Digestion, various processing methods (heating, cooking), and fermentation may influence the amount of relevant allergen in the final product. Thus, tolerance of milk in processed foods may not exclude allergy to milk in forms such as liquid milk or ice cream. (See 'Pathogenesis' above.)

Cow's milk may be initially missed as a potential allergen due to the ubiquitous nature of milk proteins (Food Allergy Research and Education [FARE]). It should also be considered as a possible contaminant in infants reacting to mixed jarred baby foods.

DIFFERENTIAL DIAGNOSIS — Differential diagnosis of cow's milk allergy (CMA) includes other food allergies, especially hen's egg allergy, since egg proteins are commonly present in the same foods (eg, pancakes, cakes, cookies, macaroni and cheese).

Other differential diagnoses include:

●Atopic dermatitis (see "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis" and "Role of allergy in atopic dermatitis (eczema)")

●Idiopathic urticaria/anaphylaxis (see "Idiopathic anaphylaxis" and "New-onset urticaria")

●Hereditary or acquired angioedema (see "Hereditary angioedema (due to C1 inhibitor deficiency): Pathogenesis and diagnosis")

●Lactose intolerance (see "Lactose intolerance and malabsorption: Clinical manifestations, diagnosis, and management")

●Toddler's diarrhea (see "Overview of the causes of chronic diarrhea in children in resource-abundant settings", section on 'Functional diarrhea in young children')

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Food allergy".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Food allergy symptoms and diagnosis (Beyond the Basics)" and "Patient education: Food allergen avoidance (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Cow's milk allergy (CMA) is the most common food allergy in young children, affecting approximately 1 to 3 percent of children <2 years of age. Milk is a less common allergen in adults, affecting approximately 0.2 percent of the adult population. (See 'Introduction' above and 'Epidemiology' above.)

●Natural history – Tolerance is achieved by the majority of children with CMA. Non-immunoglobulin E (IgE) mediated CMA tends to resolve by early childhood, whereas IgE-mediated CMA may persist into adolescence and beyond. (See 'Natural history' above and "Food allergy in children: Prevalence, natural history, and monitoring for resolution".)

●Major milk allergens – Casein and whey proteins (beta-lactoglobulin [BLG] and alpha-lactalbumin [ALA]) are the milk proteins responsible for the majority of IgE-mediated milk allergies. (See 'Pathogenesis' above.)

●Clinical features – Manifestations of milk allergy include IgE-mediated reactions such as urticaria/angioedema and anaphylaxis, mixed IgE- and non-IgE-mediated reactions such as atopic dermatitis (eczema) and eosinophilic esophagitis, and non-IgE-mediated forms of allergy that present with delayed gastrointestinal manifestations (table 1). (See 'Clinical features' above.)

●Diagnosis – Diagnosis of IgE-mediated milk allergy is based upon careful history supported by skin prick tests and in vitro tests for specific IgE. An oral food challenge is warranted if the diagnosis of milk allergy is uncertain. Diagnostic testing for non-IgE-mediated manifestations is limited. (See 'Diagnosis' above.)