Infants in the AAF group used significantly more health care resources and prescribed drugs than infants in the other two groups. The estimated costs of managing a CMA infant over the first 12 months following the start of feeding were USD 3,577, 3,781 and 6,255 for an infant fed eHF-C plus LGG, eHF-C only and AAF, respectively [48].
Rice-Based Extensively Hydrolyzed Formulas
One prospective open, randomized clinical study compared the clinical tolerance of a hydrolyzed rice protein formula (HRPF) with a CMP eHF in 92 infants (mean age 4.3 months, range 1.1-10.1 months) with IgE-mediated CMA. The HRPF was well tolerated in all infants tested, and measurement of IgE levels towards CMP during the study showed no significant differences between the two formula groups. During the follow-up (at 3, 6, 12 and 24 months), children receiving HRPF showed similar growth and development of clinical tolerance to those receiving an eHF [49].
A new extensively HRPF (eHRPF) for infants was tested in 40 infants with CMA confirmed by food challenge. All infants tolerated the eHRPF (according to a symptom-based score and growth parameters) and symptoms significantly decreased in the first month of the eHRPF intervention [50, 51].
However, the content of arsenic in rice infant formula needs to be controlled [52], and further studies with short- and long-term data on allergic reactions, nutritional adequacy and safety are needed.
Other Formulas
Adverse reactions in CMA individuals consuming soy milk have been attributed to a 30-kDa, glycinin-like protein from soybean that cross-reacts with Cas CM. The European and American guidelines do not recommend soy in infants with CMA as first option [1, 2, 53]. Tolerance to soy protein has been reported in 83-92% of the infants with CMP allergy [40, 53]. Nutritional and safety concerns are mostly related to absorption of micronutrients and phytate and isoflavone contents. More recently, a review on soy infant formula concluded it to be safe [54].
Other protein sources have been assessed in the treatment of CMA. In some countries, goat’s milk exists as commercialized infant formula and is adapted to the nutritional needs of infants. However, the cross-reactivity with CMP is about 80-90% [8]. Milk from other mammalians or chicken-based formulas cannot be recommended for the treatment of CMP allergy for limited data on tolerance, safety and nutritional adequacy [1-3].
Acquisition of Tolerance
Oral tolerance, defined as hyporesponsiveness to innocuous antigens, may be explained by T-cell anergy, clonal deletion by apoptosis and active (contact-dependent) or cytokine-mediated (immune deviation) suppression exerted by subsets of regulatory T cells [55]. Important variables with regard to oral tolerance induction include genetics, age, dose and timing of postnatal oral antigen administration, antigenic structure and composition, gut epithelial barrier integrity and the degree of concurrent local immune activation (reflected by local cytokine profiles and expression of costimulatory molecules on antigen-presenting cells; fig. 1) [55].
Most children have outgrown CMA by 3 years of age, but in a minority it can become persistent. Non-IgE-mediated allergy typically resolves earlier than IgE-mediated allergy. Conversely, high specific IgE and low IgA levels to β-Lg at diagnosis and low CM-specific IgG4 during follow-up are associated with persistent CMA [56].
In an open prospective comparative study, 260 infants diagnosed with CMA (IgE-mediated CMA in 43%) were evaluated for acquisition of tolerance. The rate of children acquiring oral tolerance after 12 months of treatment was significantly higher (p < 0.05) in the groups receiving eHF-C (43.6%) or eHF-C plus LGG (78.9%) compared with the other groups: rice HF (32.6%), soy formula (23.6%) and AAF (18.2%). Binary regression analysis (coefficient B) revealed that the rate of patients acquiring tolerance at the end of the study was influenced by two factors, the IgE-mediated mechanism (B -2.05, OR 0.12, 95% CI 0.06-0.26; p < 0.001) and the formula chosen, i.e. those receiving either eHF-C (B 1.48, OR 4.41, 95% CI 1.44-13.48; p = 0.009) or, even better, eHF-C plus LGG (B 3.35, OR 28.62, 95% CI 8.72-93.93; p < 0.001) [46].
Fig. 1. Tolerance and allergy. GALT = Gut-associated lymphoid tissue.
Nutritional Value
Impaired growth in infants with food allergy may be related both to the disease itself, causing inadequate intake or compromised absorption, and/or to inappropriate nutrient content of the dietetic regimen. The maintenance of a nutritionally adequate diet is not easy, especially in more severe cases, but is mandatory [39]. In the first 4-6 months of life, formulas represent all and in the second semester of life about half of the nutrient source, and hence nutritional appropriateness is obviously mandatory to avoid short- and long-term health consequences [39]. For optimal utilization, the hydrolyzed protein source should respond to a precise pattern of indispensable amino acids with the branched-chain amino acids and valine representing around 50% of the essential amino acid quote [57]. AAFs are also diversified within the different types of formulas, with taurine practically being the only amino acid in SFs, while branched-chain amino acids and glutamate are the major amino acids in eHF [39]. In the GINI study, the longest prospective, randomized, double-blind trial of full-term at-risk neonates, eHF-C-fed infants showed a significantly lower gain in weight and BMI than infants fed the other formulas in the first year of life. No significant differences in weight and BMI were found among the other formula groups (pHF-W, eHF-W and CM-based formula) or the breastfed group over the entire period up to 10 years of life [58].
According to adult taste, there is an inverse relation between peptide size and palatability that can influence the amount of intake compared to non- or less-hydrolyzed peptides. In infancy, eHF-C determined a significantly more savory, bitter and sour-tasting preference as long as the infants were not weaned [39]. According to adult taste, rice hydrolysates taste better than CM-based eHFs.
Conclusion
pHF and eHF represent a valid substitute of CM-SFs in infants at risk for or with CMA. The degree and method of hydrolysis, and nonnitrogen and additional