Introduction
Cow’s milk protein allergy (CMPA) is one of the most common food allergies during infancy and may develop through IgE-mediated, non-IgE-mediated, or mixed immunological mechanisms. Globally, the prevalence of CMPA ranges from 0.5% to 7.5%, with an estimated prevalence of 2–3% in developed countries [1, 2]. This high prevalence underlines the importance of proper diagnosis and follow-up. Non-IgE-mediated reactions are typically limited to gastrointestinal symptoms, have a delayed onset, and follow a chronic course, whereas IgE-mediated reactions present more rapidly with systemic and potentially life-threatening symptoms. Recent evidence suggests that a subset of infants initially diagnosed with non-IgE-mediated CMPA may later undergo immunological transition and develop IgE sensitization. This shift, which may occur during periods of antigen elimination or following mucosal immune modulation, increases the risk of severe reactions such as anaphylaxis upon re-exposure to cow’s milk proteins [3, 4].
This case is clinically significant as it describes the development of IgE-mediated anaphylaxis in an infant initially diagnosed with non-IgE-mediated allergic proctocolitis.
Case report
A 40-day-old male infant was admitted with a 10-day history of mucous and bloody stools. He was exclusively breastfed and was not receiving any formula or complementary feeding. Physical examination revealed no fever, signs of infection, or anal fissures. Stool microscopy showed no evidence of parasites or infection. Skin prick tests (SPT) for common allergens (cow’s milk, egg, wheat, hazelnut, soy, peanut) were negative. The preliminary diagnosis was allergic proctocolitis, and the mother was advised to start a cow’s milk elimination diet.
Within 48 h of initiating the elimination diet, a reduction in rectal bleeding was observed. By day 8, bleeding had completely resolved, and by day 14, the mucous content of the stool had significantly decreased. These findings supported a diagnosis of non-IgE-mediated CMPA. The mother was supplemented with calcium (1000 mg/day) and vitamin D (400 IU/day), and clinical follow-up was planned.
At the 4-month follow-up, the infant’s growth and developmental parameters were within normal limits (25th–50th percentile). Mild eczematous lesions were observed on the cheeks, for which topical corticosteroids and emollients were prescribed. Complementary feeding began at 5 months, and vegetables such as potatoes, zucchini, and carrots were well tolerated. At 6 months, the maternal diet was gradually expanded using the “milk ladder” protocol, beginning with baked milk products. No adverse reactions were observed during this period.
However, at 7.5 months of age, the mother – assuming the allergy had resolved – gave the infant one tablespoon of yogurt. Within 10 min of ingestion, erythematous, blanchable, pruritic rashes appeared on the face and trunk, followed by vomiting. The infant was brought to the emergency department, where generalized urticarial lesions and repeated vomiting led to a diagnosis of anaphylaxis. The symptoms resolved completely following intramuscular adrenaline administration. Laboratory findings revealed elevated levels of cow’s milk-specific IgE (34 kU/l) and serum tryptase (14 ng/ml; normal reference range < 11.4 ng/ml). The parents received detailed education regarding anaphylaxis and cow’s milk elimination.
Discussion
This case highlights the potential for non-IgE-mediated allergic proctocolitis to evolve into IgE-mediated systemic reactions. Although non-IgE-mediated allergies are typically expected to resolve within the first year of life, increasing sensitization in some patients may result in IgE-mediated hypersensitivity. The exact pathogenesis of the immunological transition from non-IgE- to IgE-mediated allergy remains unclear.
Food allergies are classified according to the underlying immune mechanism as IgE-mediated, non-IgE-mediated, or mixed types. In IgE-mediated allergies, IL-4 and IL-13 secreted by Th2 cells induce B cells to produce IgE antibodies. These antibodies bind to mast cells and, upon re-exposure to the allergen, trigger rapid and systemic reactions. Non-IgE-mediated allergies, in contrast, are driven by T cells, typically have a delayed onset, and are mostly limited to gastrointestinal inflammation. The transition from non-IgE- to IgE-mediated allergy arises through a complex interaction of immunological factors rather than a single pathway. In early infancy, the immature mucosal barrier allows increased antigen permeability and enhanced presentation. In genetically predisposed individuals, epidermal or mucosal barrier defects may impair the development of oral tolerance. A Th2-skewed immune response and class switching of B cells to IgE production are central to this shift. Thus, initially T-cell-mediated responses can evolve into IgE-mediated reactions under the influence of increased antigen exposure, altered cytokine profiles, and environmental triggers. Additionally, skin barrier disruption, as seen in atopic dermatitis, may facilitate transcutaneous food sensitization [5–7].
Skin prick testing is generally not recommended for non-IgE-mediated food allergies, particularly in cases of allergic proctocolitis [8]. According to a position paper by the European Academy of Allergy and Clinical Immunology on non-IgE-mediated allergies, IgE testing may be considered in exclusively breastfed infants who exhibit symptoms associated with IgE-mediated allergies, have comorbid conditions such as atopic dermatitis, or are undergoing food reintroduction after a prolonged elimination period [2]. However, in our clinic, we perform SPT in all patients at their initial presentation, regardless of the presumed immunological mechanism. In this case, retrospective review confirmed that the initial cow’s milk SPT was negative. Prior to dietary re-challenge, we routinely repeat the SPT to identify any IgE sensitization that may have developed. Although the costs and availability of such testing vary by the healthcare system and clinical setting, we balance cost-effectiveness with patient safety in our practice.
Several case reports in the literature describe infants with non-IgE-mediated CMPA who later developed IgE-mediated allergies. One case series reported that 5 children diagnosed with food protein-induced allergic proctocolitis during infancy developed IgE-mediated cow’s milk allergy during long-term follow-up, with some experiencing severe systemic reactions such as anaphylaxis and angioedema [8].
Clinicians should be aware of the potential for non-IgE-mediated allergies to evolve into IgE-mediated forms, especially when planning food reintroduction following elimination. Sensitization testing, including SPT and/or specific IgE measurement, is crucial before introducing high-risk foods to prevent anaphylactic reactions. In settings with limited access to testing, reintroduction of cow’s milk after prolonged elimination should be performed in a hospital setting, starting with baked milk products. Home-based milk ladder protocols should be conducted under the supervision of an allergy specialist. These protocols involve the gradual introduction of increasingly allergenic dairy forms. Direct administration of unheated milk or yogurt, particularly in infants without prior specific IgE testing, carries a high risk. In this case, unsupervised reintroduction by the mother resulted in a severe systemic reaction [2, 9].
Recent studies have emphasized the importance of molecular allergy diagnostic methods in the diagnosis and monitoring of IgE-mediated cow’s milk protein allergy; component-resolved approaches may contribute to identifying patients at risk of developing more severe IgE-mediated phenotypes during follow-up [10]. However, no specific and reliable laboratory parameter has yet been clearly defined to predict the transition from non-IgE-mediated to IgE-mediated allergy.
The markedly elevated specific IgE level confirmed an active IgE-mediated mechanism and suggests that future exposures could elicit similar reactions. Therefore, oral food challenges may be warranted when planning reintroduction after an elimination diet. Additionally, mild eczematous lesions observed from the fourth month of life may have contributed to sensitization. Atopic dermatitis in early childhood is both associated with food allergies and predictive of subsequent IgE-mediated sensitization. In cases with confirmed anaphylaxis, as in our patient, an epinephrine auto-injector should be prescribed and the family should receive comprehensive training [2, 9].
Conclusions
Cow’s milk protein allergy presents a broad clinical spectrum and may undergo immunological shifts over time. This case exemplifies the potential progression from non-IgE-mediated allergy to IgE-mediated anaphylaxis. Reintroduction of eliminated foods should be performed cautiously under medical supervision, and families must be actively involved in the process. All patients at risk of anaphylaxis should be equipped with an epinephrine auto-injector and trained in its use.
