APT positivity for foods and breast milk, in our case series of exclusively breast-fed infants with APC, confirms the hypothesis that food proteins can be transferred through lactation and are potentially able to induce an allergic reaction in infants [14
]. Indeed, more than 50% of cases of APC reported in literature are exclusively breast-fed infants, and in most cases a gradual and complete resolution of the disease can be observed after 72-96 hours of maternal avoidance of offending proteins [1
]. Lake reported the most common causative food is cow's milk (65%), but also egg, corn and soy can be implicated (in 19%, 6%, 3%, respectively) and about 5% of infants have an identified multiple food allergy [1
]. In our case series, APTs for foods detected a sensitization to CM in 50%, soy in 28%, egg in 21%, rice in 14%, wheat in 7%, thus suggesting that CM is probably the most common causative food in infants with APC. However, note that the APT negativity for foods eliminated from the maternal diet, such as CM, might also be due to the long period of allergen avoidance with consequent desensitization of infant. Furthermore, the positivity in all patients of APTs for breast milk of mothers on hypoallergenic (CM plus soy and/or egg-free) diets is strongly suggestive of the involvement of many allergens other than CM.
It is reported in about 12% of cases, offending foods could not be identified through maternal dietary manipulation and breast feeding maintenance led to intermittent persistent bleeding [1
]. Similarly, our patients represent that select subgroup of infants which require discontinuing breast feeding; we speculate their non-responsiveness could be due to a multiple food allergy, as shown by both the polisensitization detected by APTs in 50% of patients and the APTs positivity for BM of mothers on hypoallergenic diet. In those requiring hypoallergenic formulas, about 41% could need an AAF due to non-responsivity to extensively Hydrolized Formula (eHF). Our choice to administer an AAF, prior to trying an eHF as guidelines would recommend [20
], was based on the potential allergenicity of eHF, due to residual immunologically active proteins, in highly allergic children [21
]. This is particularly an issue for children with allergy that is not directly related to food-specific IgE antibody, such as APC. Probably the gastrointestinal allergic reactions are more likely to be triggered by residual peptides in eHF because T-cell epitopes are typically smaller than B-cell, IgE-binding, epitopes [24
]. Children with gastrointestinal food allergy, which are presumably T-cell-mediated, may therefore be more likely to react to eHF, thus representing a group for whom AAF is particularly important, as in our case series.
The diagnosis of APC is commonly based on clinical features and the response to maternal avoidance of the offending proteins. In refractory cases, we suggest to perform endoscopical examination with the aim to exclude any possible cause of rectal bleeding, other than APC, which might explain symptom persistence [2
]. The clinical suspicion of APC was confirmed in our patients by colonoscopic features and biopsies, which showed eosinophilic inflammation and LNH, which is a common finding in food allergy [13
]. After one month of elemental feeding LNH significantly decreased or completely disappeared and colonic mucosa was normal. Positive response to the AAF also suggests the presence of food allergy as the possible cause of gastrointestinal complaints. However, in our case series, the diagnostic oral provocation test was not performed for ethical considerations due to the severity of clinical findings. Rectosigmoidoscopic follow-up was considered more ethically correct to confirm mucosal healing.
To the best of our knowledge, no data is currently available on the use of APT in infants with APC. Many studies shown the ability of APT in detecting delayed food reactions in infants with atopic dermatitis, with a high specificity and poor sensitivity [27
]. Together with prick testing and serum specific IgE assay, a positive predictive value of about 95% can be attained [29
]. Its usefulness was also proposed in the diagnostic work-up of non-IgE-mediated gastrointestinal food allergy in patients with growth distrurbance, rectal bleeding and gastro-esophageal reflux disease [30
], eosinophilic esophagitis [32
] and food protein-induced enterocolitis syndrome [33
]. Positive APT, together with negative prick tests and negative serum specific IgE, suggest food proteins carried via breast milk can sensitize exclusively breast-fed infants, and then trigger a T lymphocyte-mediated allergen-specific immune response [28
]. This delayed-type hypersensitivity reaction has already been proposed as a pathogenetic mechanism of APC by Dargent et al [35
]. It has been suggested that an allergic reaction in the first week of life (as seen in our 7-day-old patient) could be due to an intra-uterine sensitization, secondary to transplacentar antigen passage [14
]. The exposure to food antigens in a sensitized infant may lead to hypersensitivity response types I, III and IV (according to Gell and Coombs' classification). Some authors suggested both intestinal immaturity and marked eosinophilic infiltration, which may significantly alter tight junctions, lead to increased intestinal permeability to food proteins [36
]. Eosinophils are often clustered in proximity to the lymphoid aggregate below an epithelial erosion, also noted in some of our patients (Figure ); this observation suggests their role in response to antigen uptake and the possible site of T cell interaction [1
]. It is thought today eosinophils may be directly responsible for tissue injury in allergic colitis and it is interesting to note that these cells can bind IgA, which are normally present in breast milk, and undergo degranulation. Eosinophil-derived mediators can stimulate a secretory response from epithelial cells in vitro; this may represent an important pathway in the development of diarrhea. The immature immune system fails to prevent the infiltration of eosinophils, leading to the destruction of epithelial cells, which are responsible for clinical features [6