September 27, 2007 — A review in the October issue of the Archives of Disease in Childhood offers recommendations to assist general pediatricians and primary care clinicians in diagnosing and managing cow's milk protein allergy (CMPA) in breast-fed and formula-fed infants. The study authors emphasize the importance of evaluating these recommendations using clinical audit standards, such as the number of children with symptoms, growth and developmental milestones, and percentiles for height and weight.

"Between 5% and 15% of infants show symptoms suggesting adverse reactions to cow's milk protein (CMP), while estimates of the prevalence of cow's milk protein allergy (CMPA) vary from 2% to 7.5%," write Yvan Vandenplas, from the Universitair Ziekenhuis Brussel Kinderen, Vrije Universiteit Brussel in Brussels, Belgium, and colleagues. "Differences in diagnostic criteria and study design contribute to the wide range of prevalence estimates and underline the importance of an accurate diagnosis, which will reduce the number of infants on inappropriate elimination diets. CMPA is easily missed in primary care settings and needs to be considered as a cause of infant distress and diverse clinical symptoms."

The objective of this review was to develop guidelines for pediatricians and primary care clinicians to assist them with the diagnosis and management of CMPA in infants. The basis for these recommendations included whatever limited evidence was available from the literature; discussion based on current national recommendations and standards from Germany, the Netherlands, and Finland; and clinical experience of a task force recruited by the corresponding study author.

An immunologic reaction to 1 or more milk proteins is the cause of CMPA, differentiating CMPA from lactose intolerance and other adverse reactions to CMP.

Because CMPA can develop in exclusively and partially breast-fed infants, and when CMP is introduced into the feeding regimen, the guidelines provide separate algorithms detailing diagnosis and management of CMPA in breast-fed and formula-fed infants. The algorithms also differ based on the severity of symptoms.

Diagnosis begins with a thorough history, including a family history of atopy, and a complete physical examination to rule out other causes, to identify any comorbid conditions, and to classify the CMPA as mild to moderate or as severe. For infants with severe symptoms, referral is recommended to a specialist experienced in managing childhood allergies. The gold standards for diagnosis are eliminating CMP from the infant's or mother's diet and subsequent challenges by reintroducing CMP into the diet.

Blood-stained stool in an infant is usually benign and self-limited, is observed primarily in exclusively breast-fed infants, and is sometimes associated with viral infection. Because cow's milk allergy in these infants is less frequent than was previously thought, cow's milk challenge is indicated for infants who become symptom-free during a CMP-free diet. Such challenge will decrease the number of false-positive diagnoses of CMPA.

When symptoms recur after dairy products are reintroduced into the mother's diet, the algorithm recommends extensively hydrolyzed formula if the mother wishes to begin weaning the infant and if the child is between 9 and 12 months of age.

For formula-fed infants, skin prick tests, patch tests, and specific IgE determination may assist diagnostic evaluation and guide management in some cases. However, in formula-fed infants as well as in breast-fed infants, elimination diets and challenges are the gold standards for diagnosis of CMPA. Therefore, the task force recommends open challenge, both for simplistic as well as for socioeconomic reasons.

When the outcome of open challenge is inconclusive, a double-blinded, placebo-controlled challenge may be useful. To reduce the costs of a diagnostic evaluation, a radioallergosorbent test, skin prick test, or both may be performed only in those infants responding to an elimination diet, either to guide the challenge or to predict the prognosis more accurately after a positive challenge.

Breast-feeding is the preferred method for nourishing healthy infants. Accurate, timely diagnosis and appropriate management of CMPA, including adequate treatment, will reassure parents and reduce the risk for impaired growth.

Infants with mild to moderate symptoms should be fed extensively hydrolyzed formulas, or amino acid formula if extensively hydrolyzed formula is refused or if the cost-benefit ratio favors amino acid formula, for 2 to 4 weeks or longer. Those infants with a significant improvement or resolution of symptoms should undergo a medically supervised challenge. If CMP challenge leads to reappearance of symptoms of CMPA, the child should be maintained on extensively hydrolyzed formula or amino acid formula for 6 months or more or until reaching 9 to 12 months of age.

Symptoms that fail to improve with extensively hydrolyzed formula should lead clinicians to consider an elimination diet with amino acid formula, other differential diagnoses, or both. In this case, a pediatric specialty referral is recommended.

In a formula-fed infant, suspected severe CMPA should be managed with amino acid formula and a pediatric specialty referral. Infants with severe symptoms should undergo food challenges only in a medical setting in which personnel are experienced in treating anaphylaxis. The study authors caution clinicians to be aware that after a period of dietary elimination, patients with previously mild to moderate reactions may develop severe reactions.

Unmodified mammalian milk protein (cow, sheep, buffalo, horse, or goat) or unmodified soy or rice milk is not recommended for infants because they lack sufficient nutrition to be the sole source of food for infants, and they run the risk for possible allergenic cross-reactivity.

To reflect local differences in practice settings and conditions, these recommendations may need to be adapted. Because the paucity of available evidence mandated reliance primarily on expert opinion, the study authors note that these guidelines should be prospectively validated and revised as needed.

"National or regional organisations should ensure that education is provided for families regarding a milk avoidance diet," the study authors conclude. "Health care providers should be instructed about rescue medications such as antihistamine use and adrenaline in case of accidental exposure to the offending antigen(s), especially in infants with IgE-mediated allergy.... Once validated, we hope the diagnostic framework could provide a standardised approach in prospective epidemiological and therapeutic studies."

SHS/Nutricia funded development of these guidelines. Some of the authors have disclosed financial relationships with SHS/Nutricia, Mead Johnson, Nestle, Janssen Pharmaceuticals, Astra, Wyeth, and Biocodex.

Arch Dis Child. 2007;92:902-908.

Clinical Context

Study Highlights

• CMPA most frequently causes symptoms in the gastrointestinal tract, such as regurgitation, vomiting, and changes in the pattern of bowel movements, as well as dermatologic symptoms including atopic dermatitis, angioedema, and urticaria. Symptoms of the respiratory tract are less common.
• Breast-feeding should be the sole means of milk-feeding for at least the first 4 months of life. Breast-feeding significantly reduces the risk of developing CMPA. If a breast-fed infant develops symptoms of CMPA, the mother should consider exclusion of cow's milk, peanuts, and hen's eggs from her diet. Such an exclusion diet should be continued for at least 2 weeks before judging its effectiveness or up to 4 weeks in cases of atopic dermatitis or allergic colitis.
• If symptoms improve after implementation of an elimination diet, the nursing mother may reintroduce 1 food into her diet per week. If there is no improvement after an elimination diet, referral to a specialist with experience in pediatric allergy should be considered.
• Among formula-fed children, suspected mild or moderate CMPA may be diagnosed by implementation of a formula based on extensively hydrolyzed proteins or other amino acids. Although amino acid formulas may be more expensive, IgE-mediated reactions have been documented with the use of extensively hydrolyzed formulas. During this elimination diet, the use of other supplementary foods should be limited as much as possible.
• Skin prick tests and radioallergosorbent testing neither prove nor disprove the diagnosis of CMPA, so elimination diets and food challenges are the best means of diagnosis. However, these serologic markers can be helpful in predicting the course of the illness.
• If symptoms substantially improve after a trial of an elimination diet among formula-fed children with mild or moderate symptoms of CMPA, a challenge with a formula based on CMP should be performed. This challenge should be performed with medical supervision and begins with only a drop of formula on the child's lips, with a gradual increase in the amount of formula feeding once every 30 minutes. Among children with more severe symptoms, formula challenges may be performed only after skin prick or radioallergosorbent testing against CMP improves.
• If the formula challenge confirms CMPA among formula-fed children, an elimination diet with extensively hydrolyzed formula or amino acid formulas should be used for at least 6 months.
• Formula-fed children with suspected severe CMPA should be referred to a pediatric specialist and should receive amino acid, not extensively hydrolyzed, formula.
• The use of unmodified mammalian milk protein from any animal is not recommended during infancy because these milks do not provide adequate nutrition for a growing child. Soy protein formulas are not necessarily hypoallergenic, and extensively hydrolyzed formulas or amino acid formulas are preferred for the alimentation of children with CMPA.

Pearls for Practice

• CMPA is an immunologic disorder that may or may not be mediated by IgE. Children who are serologically positive for CMPA are at increased risk for a longer duration of symptoms as well as other atopic diseases.
• The criterion standards of diagnosis of mild to moderate CMPA are elimination diets and food challenges.

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