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Cow's Milk Allergy in Children

Editor's Note: The "Cow's Milk Allergy in Children" manuscript was submitted by the late Cassim Motala, MD and kindly updated and completed on his behalf by Alessandro Fiocchi, MD. Professor Motala was a member of the WAO Web Editorial Board and contributed his time and knowledge of pediatric allergy to many of WAO's initiatives.

Posted: October 2011
Updated: July 2012

	Cassim Motala, MD School of Child & Adolescent Health University of Cape Town and Red Cross War Memorial Children's Hospital Capetown, South Africa
	Alessandro Fiocchi, MD Paediatric Division Department of Child and Maternal Medicine University of Milan Medical School at the Melloni Hospital Milan, Italy

Introduction

The estimated prevalence of cow's milk allergy (CMA) varies between 0.25% and 4.9%, being higher in children than adults.¹ The prevalence is higher in referral populations, depending on the nature of the basic condition. For instance, in a consecutive series with moderate atopic eczema referred to a University-affiliated dermatology department, SPT showed 16% of infants with IgE against CMP.² In a group of infants and children with AD and no other allergic manifestations, 37% had a diagnosis of CMA.³ Cow's milk allergy can develop in exclusively or partially breast-fed infants, when cow's milk protein is introduced into the feeding regime. The incidence of CMA is lower in exclusively breast-fed infants compared to formula-fed or mixed-fed infants, and clinical reactions in the breast-fed group are mostly mild to moderate. This might be related to lower levels of CMP in breast milk compared to cow's milk. Immunomodulators in breast milk and differences in gut flora between breast-fed and formula-fed infants may also play a role.

Pathogenesis

CMA results from an immunological reaction to one or more milk proteins. This immunological basis distinguishes CMA from other adverse reactions to cow's milk protein such as lactose intolerance. CMA may be immunoglobulin E (IgE) or non-IgE-mediated and may be a manifestation of the atopic diatheses and multiple food allergies. Reactions to other foods (depending on the regional dietary intake) may occur in combination with CMA. Non-IgE-mediated disorders usually involve T-Cells (or eosinophils), present mainly with gastrointestinal symptoms and are less likely to develop multiple food allergies. IgE- and non-IgE-mediated mechanisms may play a role in the pathogenesis of atopic dermatitis and the eosinophilic gastrointestinal disorders (EGIDs).

Clinical Manifestations

The clinical manifestations of CMA depend to a great extent on the type of immunological reaction involved.

Immediate reactions

These occur <2 hours after ingestion. The most frequent manifestations are IgE-mediated cutaneous (urticaria, angioedema, acute flare-up of atopic eczema) and gastrointestinal (vomiting, diarrhea, colic) reactions. Cow's milk protein-induced enterocolitis syndrome is an immediate-onset, non-IgE-mediated, condition. It is characterized by initial symptoms occurring during the first months of life as repeated vomiting episodes sometimes leading to dehydration. Symptoms might be very severe and mimic sepsis. A characteristic feature of this syndrome is a symptom free interval of up to several hours between ingestion of milk, most often a cow's milk protein-based formula, and the first symptoms.⁴ Respiratory manifestations (asthma, allergic rhinitis) are infrequent, especially as isolated symptoms. There is a belief among some members of the lay public that the consumption of milk and dairy products increases the production of mucus in the respiratory tract – there is no scientific confirmation of this.⁵ Anaphylaxis is the most severe manifestation. Currently defined as "a severe systemic or generalised severe allergic reaction",⁶ this potentially life-threatening condition greatly adds to the burden of living with milk allergy. Diagnostic criteria include sudden onset involving skin, mucosa, or both, with at least one respiratory symptom such as dyspnoea, bronchospasm, stridor, PEF reduction, hypoxemia, fall in blood pressure, organ dysfunction symptoms (hypotonia, syncope, etc), gastrointestinal symptoms (colic, vomiting) and shock.⁷ This happens almost immediately (within minutes and up to two hours) after the ingestion of cow's milk or dairy products and is clinically similar to anaphylaxis from foods different from CM.⁸

Delayed reactions

These immunological, non-IgE-mediated reactions occur several hours or days after milk consumption. Atopic dermatitis is observed in approximately 10-15% of young children. It is primarily because of the dryness of skin and is linked to hereditary factors; however, approximately one third of patients with moderate to severe atopic dermatitis present with flares of eczema linked to a food allergy.⁹ Cow's milk, hen's egg, and peanuts are the foods most frequently involved. GI disorders include food protein-induced (FPI) enterocolitis, enteropathy and proctolitis.¹⁰ Milk induced proctocolitis is mostly observed in young infants while exclusively breast-fed.¹¹ FPI disorders are typically cow's milk and soya protein induced, but they may also occur with ingestion of solid foods including, fish, chicken, turkey, corn and vegetables. FPI-enterpathy usually presents with diarrhea, mild to moderate steatorrhea (80% of cases) and poor weight gain. The clinical signs of secondary lactose intolerance, including perianal excoriation from acidic stools, may be present.¹² Rectal bleeding is the usual presenting feature of FPI-colitis. The infant is otherwise well and thriving. The eosinophilic gastrointestinal disorders (EGIDs) include eosinophilic esophagitis, gastritis, gastroenteritis and colitis. While in children symptoms of eosinophilic esophagitis are similar to gastroesophageal reflux, in adults dysphagia and food impaction is common. Symptoms of EGIDs are usually chronically relapsing and the clinical presentation includes failure to thrive (due to chronic diarrhea, refusal of food and/or vomiting); iron deficiency anemia (due to occult or macroscopic blood loss); and hypoalbuminemia or recurrent abdominal pain. A rare form of milk reaction is Milk-Induced Chronic Pulmonary Disease (Heiner's Syndrome), characterized by recurrent pulmonary infiltrates associated with chronic cough, recurrent fever, tachypnea, wheezing, rales, failure-to-thrive and family history of allergy caused by cow's milk ingestion.¹³

Diagnosis

Clinical evaluation

A comprehensive history (including a family history of atopy) and careful physical examination form the foundation for the diagnosis and management of CMA. Unfortunately, there is not one symptom that is pathognomonic for cow's milk allergy, but the timing and pattern of symptoms aid the diagnosis. For instance, in a patient that presents an acute anaphylaxis after ingestion of milk without another food or trigger, there is a very strong clinical suspicion. Symptoms of CMA occur often, but not always, within the first weeks after the introduction of cow's milk proteins. Many of the children with cow's milk allergy develop symptoms in at least two of the following organ systems: gastrointestinal (50-60%), skin (40-50%) and respiratory tract. Temporal relationship between milk ingestion and onset of symptoms should also be assessed to distinguish immediate from non-IgE-mediated reactions.

Diagnostic tests

IgE-mediated CMA. Skin-prick testing (SPT) with fresh milk or commercial reagents and ImmunoCAP-RAST (for determining specific IgE against cow's milk proteins as caseins, lactoglobulin, and alpha-lactalbumin), are the currently available tests. The performance characteristics of these tests have been described in different settings. In children older than two years, an SPT reaction with a wheal diameter ≥8mm¹⁴ or milk specific IgE level ≥¹⁵,0 ku/L, the likelihood is 95% that the child will have a positive milk challenge. The corresponding wheal size in children younger than two years is 6mm diameter⁵ and milk-specific IgE ≥5,0ku/L¹⁶ respectively. Studies on specific caseloads are limited by several factors inherent to the characteristics of the studied group, such as clinical conditions (AD, asthma, GI), their severity, the percentage of polyallergic patients, and age and geographical differences.¹⁷ Thus, the use of sensitization tests is dependent on the clinical setting and on the pre-test probability of disease. For this reason, the whole matter has been subjected to systematic review and metanalysis in the preparation of the Diagnosis and Rationale Against Cow's Milk Allergy (DRACMA) guidelines. Including studies published up to September 2009, the DRACMA panel reviewed the evidence summaries and the draft guidelines, and made recommendations on diagnosis.

According to these recommendations,

A formal challenge with cow's milk remains the best diagnostic test.
It should be performed with physician supervision regardless of food-specific IgE value.
If challenge is positive, out of a research setting sensitization tests may not be necessary.
In settings where oral food challenge is not considered a requirement for making a diagnosis of IgE-mediated cow's milk allergy, a positive SPT and/or ImmunoCAP (cut-off: 0.35 kUI/L) can be used and diagnostic tests in case of high pre-test probability.
In such settings, a negative SPT and/or ImmunoCAP with whole milk (cut-off: 0.35 kUI/L) can be used as rule-out tests in case of low pre-test probability.
In any case of high uncertainty, challenges remain necessary.

The prognostic and diagnostic utility of using specific proteins at ImmunoCAP or microarrayed platforms remains to be established.¹⁸

Non-IgE-mediated CMA: There are no reliable tests for the diagnosis of non-IgE mediated CMA. Initial diagnosis is based on a suggestive history and absence of positive SPT or ImmunoCAP-RAST. In these patients, the diagnosis primarily relies on a successful milk avoidance diet with clinical relapses after re-exposure to cow's milk proteins. In patients with atopic dermatitis and eosinophil esophagitis in whom non-IgE mediated cow's milk allergy is suspected, Atopy Patch testing (APT) may be a helpful diagnostic tool.¹⁹

Elimination-challenge testing: Food challenges remain the definitive procedure for the diagnosis of CMA. If the symptoms substantially improve or disappear after 2-4 weeks on an elimination diet, an open challenge with a formula based on whole cow's milk protein should be performed. Clinicians should be aware that the severity of a past reaction might not predict the severity of a challenge reaction, particularly after a period of dietary exclusion. Previous mild reactions may be followed by anaphylactic reactions in some infants with CMA. For this reason, open challenges should ideally be performed in a setting where resuscitation facilities are available. In a case of cow's milk-induced anaphylaxis, a challenge is contraindicated unless SPTs and/or specific IgE measurements show improvement. In these cases, the challenge should always be performed in a hospital setting.

Positive challenge: CMA confirmed

If symptoms of CMA re-appear, the suspected diagnosis of CMA is confirmed and the infant should be maintained on an elimination diet using a milk substitute (discussed below) for at least 6 months. The challenge is then repeated. If it is possible to follow the infant with IgE-mediated allergy with SPTs and/ or specific IgE determination, improvement of these tests would help in choosing the time point of challenge. Supplementary feeding should be introduced carefully to avoid accidental intake of cow's milk protein. Protocols of milk challenges have been published in different guidelines.^{1, 20, 21} Of importance, all guidelines emphasize the rules for milk challenge in immediate CMA, while the interpretation of delayed reactions occurring up to 7,²² 9,²³ or 14 days²⁴ is more controversial. The diagnosis of delayed reaction may be difficult because when the child returns home, multiple environmental factors (infections, dietary factors, emotional, casual contacts, sports-related physical activity) may impinge diagnostic interpretation. Frequently, immediate and delayed symptoms are present concomitantly in the same child.²⁵

Negative challenge: No CMA

Children who do not develop symptoms on the cow's milk formula during challenge and up to one week after follow-up can resume their normal diet, although they should still be carefully monitored. Clinicians should advise parents to be attentive for delayed reactions, which may evolve over several days following the challenge.

Treatment of Cow's Milk Allergy in Children

Avoidance of cow's milk protein

Patients with cow's milk allergy must strictly avoid cow's milk and cow's milk protein-based products. Patients and their families must be instructed to read labels and identify milk-containing products. Particularly in young children, a well-balanced diet with sufficient intake of calcium and other essential nutriments must be warranted. The input of a paediatric dietician is most helpful in these patients. Mothers of breast-fed infants with CMA should continue breast-feeding but avoid causal foods. Recent studies raise the question of the possibility of following an incomplete milk avoidance in less severe cases of CMA. Children receiving limited, extensively heated milk reported no acute milk-induced allergic reactions as a result of this diet, suggesting that a change from a milk avoidance diet to a milk-limited diet could provide a substantial improvement to the quality of life of milk-allergic individuals.^{26, 27} Moreover, baked milk tolerant consuming baked products have been recently indicated more likely to have unheated milk tolerance than subjects not consuming such products.²⁸ This is in conflict with the observation that CMA children exposed to little doses of milk proteins in eHF may display a longer duration of CMA.²⁹ Thus, exposing such children to milk allergens remains an unwarranted practice.

The literature does not report a single case of an adverse reaction to lactose ingestion among children with CMA, and a prospective study of the allergenicity of whey-derived lactose investigated by serology and DBPCFC did not document such reactions.³⁰ Thus, even if lactose ingestion may per se carry risks of cow's milk protein contamination (as seen from incidents after inhalation of lactose-containing drugs³¹) the total elimination of lactose from the diet of children with CMA is not warranted.

Conversely, beef allergy is possible in children with CMA.³² While almost all children allergic to beef are also allergic to milk,³³ industrial treatment, more than home cooking, may modify the allergic reactivity of this meat in beef-sensitive children,³⁴ thus making industrially freeze-dried or homogenized beef safe alternatives to butcher's meat cooked at home. Again thus, although beef allergy should be considered, total avoidance of beef by all children allergic to cow's milk is not justified.

Alternate formula (milk substitutes)
See Table 1

The recently published international guidelines^{1, kemp} recommend extensively hydrolyzed formulae (eHF) or amino-acid based formulae (AAF) as first line alternatives for children with CMA. In general, eHFs are nutritionally adequate and well-tolerated by children allergic to cow's milk and other foods but their main drawbacks are their bitter taste, expense (2-3 times the cost of standard formula), and their potential to cause anaphylaxis. As such formula are obtained from casein or whey proteins, residual antigenic activity has been found in all types of extensive hydrolysates by both in vitro and in vivo studies, which show that any formula may potentially trigger reactions in infants allergic to cow's milk.³⁵ Current guidelines define a therapeutic formula as one that is tolerated by at least 90% (with 95% confidence) of CMPA infants.³⁶ The antigenicity and allergenicity of hydrolysate formulae is partially dependent on their molecular weight, even if prevention studies demonstrate that formulae with a higher mean molecular weight may be associated with a better outcome in prevention of CMA,³⁷ and the definition of hypoallergenic formula does not rely on the molecular weight. Rice-hydrolized formula (RHF) are considered a second-line resource due to their not universal availability.¹ Where available, RHF can be considered instead of eHF. AAFs are safe and palatable but are exorbitantly expensive (6-8 times the cost of eHFs) and not widely available. Reimbursement for AAFs by health funders is also a potential problem as they are not generally considered as therapeutic agents. Soy formula is well tolerated in up to 85% of infants with IgE-mediated CMA but only in 50% of those with non-IgE mediated CMA. However, soya is not recommended in infants below 6 months because of concerns about possible hormonal effects on the reproductive system (shown in animal studies)- presumed due to phyto-oestrogens in the form of isoflavones (genistein,diadzen and their glycosides) present in soya protein. To date, no studies have evaluated safety of soya formula in humans-such studies are much needed.

Table 1. Choosing the appropriate substitute formula in different presentations¹

Clinical presentation	1st choice	2nd choice	3rd choice
Anaphylaxis	AAF⁺	eHF^#§	SF
Immediate gastrointestinal allergy	eHF^§♭	AAF^/SF^°
Food protein-induced enterocolitis syndrome (FPIES)	AAF	eHF*
Asthma and rhinitis	eHF^§♭	AAF^/SF^°
Acute urticaria or angioedema	eHF^§♭	AAF^/SF^°
Atopic dermatitis	eHF^§♭	AAF^/SF^°
Gastroesophageal reflux disease (GERD)	eHF^♭	AAF
Allergic eosinophilic oesophagitis	AAF
Cow's milk protein-induced enteropathy	eHF^§♭	AAF
Constipation	eHF^♭	AAF	Donkey milk^‡
Severe irritability (colic)	eHF^♭	AAF
CM protein-induced gastroenteritis and proctocolitis	eHF^♭	AAF
Milk-induced chronic pulmonary disease (Heiner's syndrome) **	AAF^	SF	eHF

⁺ recommendation 7.1
^♭ recommendation 7.2
* if AAF refusal
^§ subject to local availability, HRF can be considered instead than eHF (7.4)
^# subject to a negative SPT with the specific formula (panel recommendation)
^{^} AAF if a relatively high value on avoiding sensitization by SF and/or a low value on resource expenditure are placed.
^° SF if a relatively low value on avoiding sensitization by SF and/or a high value on resource expenditure are placed.
** this suggestion attributes a high value on avoiding exposure to even residual antigenic cow's milk proteins.
^‡based on reports from one case series³⁸
⁺given that more than 50% of such children are allergic to soy, a careful clinical evaluation is necessary (panel recommendation)¹

Milk substitutes not recommended for treatment of CMA

Partially-hydrolyzed formulae (pHF) are contra-indicated in the treatment of CMA because of the high content of residual allergen (only 12-26% of cow's milk protein is hydrolyzed in the currently available pHFs) and a definite risk of allergic reactions to these products. By definition, they do not meet the AAP standards for hypoallergenicity. Goat, sheep, buffalo, horse milk, and whole rice milk are also not recommended - these milks are not nutritionally adequate and often cross-react with proteins in cow's milk.

Specific oral tolerance induction

Avoidance is difficult as cow's milk protein is ubiquitous and accidental allergic reactions in children with CMA are common.^{nowak, 22} Specific oral tolerance induction (SOTI) or desensitization is a promising therapy for IgE-mediated.³⁹ Randomized controlled trials have reported that about 35% of children become fully tolerant to cow's milk protein after SOTI; 15-20% may not complete the procedure because of severe adverse reactions; no fatal events have been documented. Follow-up data on children who became tolerant to cow's milk protein is inadequate and it is unclear where tolerance is transient on permanent.⁴⁰ Patients undergoing SOTI require careful monitoring. Various protocols have been described, some audacious and some prudent and the procedure is very time consuming. For these reasons, SOTI should be regarded for now as experimental therapy and must only be undertaken by practitioners who have been trained in this procedure.¹

Natural History

Earlier studies reported a good overall prognosis for CMA (developing tolerance to cow's milk protein), with most children outgrowing their allergy by 3 years of age. However, the prognosis appears to vary depending on whether the CMA is IgE-mediated or non-IgE-mediated, the titre of specific IgE at the time of diagnosis and the age of onset of CMA. The most important factor is the nature of study. In birth cohorts, CMA was estimated to run its course within one year.⁴¹ Children with delayed reactions were found to develop tolerance sooner than those with immediate reactions, and these children are also less likely to develop multiple food allergy or allergy to inhalants.⁴² Referral, prospective studies indicate that in most cases (80 percent) tolerance is achieved within 3 to 4 years.^{12, 43, 44} In a cohort of pediatric patients referred to a tertiary center in Italy for DBPCFC to cow's milk, the median duration of CMA was 23 months while 23 percent of children acquired tolerance 13 months following diagnosis and 75 percent after 43 months. The longer duration has been found in retrospective referral studies. A study reported that less than half of the children diagnosed with IgE-mediated CMA during the first nine years of life outgrew it.⁴⁵ A retrospective study involving 807 patients with IgE-meditated CMA reported resolution rates as follows: 19% by age 4 years, 42% by age 8 years, 64% by age 12 years, and 79% by 16 years.⁴⁶ Children of all ages with very high levels of specific IgE are likely to have persistent milk allergy. Onset of CMA in infancy has the most favorable prognosis. In persistent disease, casein sensitization^{Garcia-Ara 38} and the presence of IgE against linear epitopes⁴⁷ have been demonstrated.

Follow-up

Follow-up and re-evaluation of CMA is important. Follow-up assessment should include: adherence to diet, growth monitoring, control of co-existing disorders, reinforcement of key educational messages e.g., reading food labels, preparedness for emergencies. Periodic re-challenges should be conducted to monitor tolerance (6-12 monthly). In cases of IgE-mediated CMA, milk-specific IgE levels should also be monitored periodically. Declining levels of specific IgE correlate well with development of tolerance.^{14, 48} Although a specific IgE level for cows milk protein of 2ku/L has been reported to predict a 50% chance of passing a challenge test,⁴⁹ systematic reviews have shown that this is not universally applicable.

Conclusions

Cow's milk allergy is one of the most frequent manifestations of food allergy and may present as an IgE- or non-IgE-mediated disease. Patients with IgE-mediated CMA and asthma are at risk of potentially severe allergic reactions (anaphylaxis). The diagnosis of CMA relies primarily on clinical evaluation supported by skin prick testing and in vitro measurement of specific IgE. CMA can be adequately treated with dietary manipulation including avoidance cow's milk protein products. All cases of CMA must be managed in collaboration with an experienced dietician who has expertise in food allergy. The dietician's role is to provide advice/recipes/education (reading food labels, checking for hidden ingredients, etc.) and to ensure nutritional adequacy. The condition can be handled at the primary level, but whenever possible it should be referred to a specialist with expertise in allergy. This becomes mandatory in severe cases of cow's milk allergy.

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