Cow’s milk allergy (CMA) is among the most common food allergies in children, with, for example, a prevalence of 1.8% in children aged 1 to 5 in the United States (1). CMA is divided into IgE mediated and non-IgE mediated CMA, although the European Academy of Asthma, Allergy and Clinical Immunology (EAACI) has recently suggested a more complex nomenclature, focusing on the underlying immunology (2). Diagnosis of CMA includes taking a clinical history, deciding on appropriate testing, followed by an oral food challenge (OFC) for IgE-mediated CMA or a period of avoidance followed by reintroduction/OFC for non-IgE mediated cow’s milk allergies (FPIES, Eosinophilic Esophagitis [EoE], FPIAP). According to the recent EAACI guidelines “A medically supervised oral food challenge (OFC) is recommended to confirm or exclude food allergy in patients with an unclear diagnosis despite IgE-sensitization tests (high certainty of evidence)” (3). Current management strategies include individualized avoidance of foods containing cow’s milk (CM), and precautionary advisory labelling. Depending on age, a hypoallergenic formula or plant-based substitute is recommended (4). For IgE-mediated CMA, emergency medications including epinephrine are used to treat anaphylaxis to CM. For IgE-mediated CMA, oral and epicutaneous immunotherapy can be used to increase tolerance in children but is not without risk, and the long-term outcome of sustained unresponsiveness is still unclear (5) (Waserman et al., 2023, Submitted)¹. Many guidelines have recently been published to improve the diagnosis, management, and treatment of CMA (3, 6–7) (See footnote 1).

Prognosis is favorable for all types of CMA. For IgE-mediated CMA, approximately 80% of children outgrow their allergy by age 6 (8). It has been known for some time that children with CMA can often tolerate baked forms of the food, especially when combined with a flour matrix (9, 10) while still demonstrating symptoms to unbaked forms, with some studies reporting as much as 70% of CMA children tolerating BM (11–15).

At this time it remains a standard recommendation to offer an observed OFC to baked milk (BM) followed by continued home ingestion of similar products (16–18). However, even after tolerance of BM in an OFC setting, a significant number of patients continue to avoid BM. Dunlop et al. reported 28% of patients sent home with a plan for BM ingestion were avoiding CM in all forms 2 to 7 years later (19). Hicks et al. have recently conducted an international survey of children who had successfully passed a BM challenge and were instructed to introduce BM at home. It was indicated that 88% of participants were instructed to eat any BM-containing food or suitable commercial option. Still, only 27% were given suitable recipes, and the majority received only 1–2 recipes, demonstrating first-hand the need for improved, standardized guidance for families regarding the home introduction of BM (20). For non-IgE mediated CMA, the use of BM in the management of FPIES and EoE have been poorly studied, with two studies indicating that BM foods may be suitable in these patient populations (21, 22). An alternative approach is an at-home food “ladder” approach, used safely in milder forms of non-IgE mediated CMA such as FPIAP (23).

One of the most impactful findings in the management of IgE-mediated CMA is the recent finding from Ireland indicating that BM can be introduced at home in infants using a milk ladder approach (7, 9). One study indicated that 65% of children safely consumed CM 12 months post randomization using a milk ladder approach, and 86% were safely consuming baked foods at 6 months post randomization (7). This review offers recommendations on facilitating safe use of milk ladders for clinical use in IgE-mediated CMA to improve future management of CMA.

CM contains a range of proteins of which 80% are casein proteins and 20% whey proteins. The allergenicity of these proteins are affected differently by different forms of heating, leading to the use of BM or milk ladders in the management of CMA. For example Bos d5 (beta-lactoglobulin) is found to be reduced by 99% with baking, whereas Bos d11 (b-casein) is reduced only by 30% (4, 24).

A food ladder is a stepwise progression from extensively heated to less heated food. Heating decreases the allergenicity of food proteins in egg and milk by degrading (altering) conformational epitopes so that the immune system has a reduced ability to recognize them (25). Heating has some but a limited effect on linear epitopes (25). Thus, it is assumed that progressing from extensively baked to less heated foods offers a progression from a less-allergenic to a more-allergenic form of the food protein. Food ladders also consider the amount of allergenic protein in each step of the ladder, which progressively increases as the ladder advances.

The first published ladder was created in 2013 for non-IgE mediated CMA (26) in the United Kingdom (UK) by Venter et al. This ladder initially contained 12 steps focusing on common British foods and was updated to a shortened ladder in 2017 that was more internationally focused regarding foods recommended (23). This ladder has been widely adopted for non-IgE-mediated CMA (27). Although initially created for non-IgE-mediated allergies, many providers also use ladders for progressive induction of tolerance at home for IgE-mediated allergies, especially to egg and CM (28). For example, one international survey found that as many as 60% of healthcare professionals responding to the survey used CM ladders for IgE-mediated food allergies (27).

There is evidence, although limited, demonstrating the development of tolerance via ladders. There have been recent publications regarding the use of home egg and CM ladders in Ireland, where pediatric allergy resources are limited, showing the safe use of a multi-step ladder. A significant number of participants achieved tolerance of egg or CM in all forms at the end of the study, even within the first year of life (28, 29). These studies were not controlled trials and included small sample sizes, limiting their generalizability.

Given that food ladders entail offering a child a known food allergen in the home, they come with inherent risk. Prior small-scale, non-randomized controlled trials (RCT) studies have reported their safe use, but the true risk of home-use of a food ladder has not been characterized (28), nor has it been described who may tolerate a ladder and who may not.

Additionally, home preparation of a ladder is not without risk, with the possibility that the amount of the allergenic protein differs from batch to batch of the same recipe or commercial food product. Further, the allergenic protein can even vary within a single serving, with the middle portion of the food being at higher risk for underbaking. Hindley et al. noted that in a BM muffin used in OFCs for CMA, baking partially denatured Bos d 11 (casein) at the periphery and had little effect on Bos d 11 in the remainder of the muffin. Bos d 5 (b-lactoglobulin) was more effectively denatured throughout the muffin (24). Thus, a ladder that could be safely used in IgE-mediated CMA would ideally have clear, simple instructions and have undergone some standardization in regard to the amount of food protein from batch to batch.

A published rostrum by Venter et al. (30) reviewed the current scientific basis for food ladders, their benefits and risks, and recommendations for the future. Possible benefits to using a ladder approach for IgE-mediated food allergy include (1) hastening of resolution of a food allergy (18), (2) increased diet diversity (31), (3) less healthcare utilization, (4) decreased cost, and (5) decreased patient burden (30). The rostrum also recommended standardization of food ladders regarding the allergenic protein content and cooking instructions for recipes, consideration of nutritional and health value of foods, acceptance of the food by a pediatric patient, and consideration of local/cultural eating practices. A review of the pros and cons of the use of ladders in IgE-mediated CMA is reviewed in Table 1.

When considering the various currently available CM ladders, which are examined individually in the following section, it is important to consider aspects related to the ladder itself; the patient/family in question; the healthcare system in which the patient exists; and the ladders impact on the patient’s nutrition, outside of allergen exposure.

Multiple food ladders are currently available for use. Though many factors have been discussed above relating the safe use ladders, ultimately the safety of ladders depend on whether the steps are planned on calculated sequential increase of allergenicity, and ideally, if the allergenicity of the different steps have been tested (see Figure 1; Table 2).

Ladders offer unique aspects that make them a desirable method of allergen introduction in some children with CMA. However, ladders are not without risk and dependent on the particular patient and ladder in use. We offer the following recommendations for the favorable use of ladders.

Patient selection is of utmost importance in the safe use of ladders. Ladders can be readily utilized in children with non-IgE mediated allergy, excluding FPIES, for a gradual introduction of a previously avoided food (35). In the setting of IgE-mediated allergy, the patient ideally will have a history of prior mild reactions to CM and a higher prior tolerance level, although again prior reactions are not clear indications of any future reactions. The patient’s comorbid conditions including asthma must be well managed to prevent more severe potential reactions. No language or comprehension barriers should exist, and families should have the time and resources needed to use the ladder. Families should also have education on reaction management, should have emergency medications in the home and should have ready access to emergency services. Lastly, a younger age may be preferred as older patients may be prone to persistence of allergy (30).

Aspects of the ladder design also must be considered for successful use. Ladders should offer clear information on food allergen content. This should include calculation and ideally measurement of the allergenic protein content. The ladder should include similar items in terms of allergenic protein content in each step, with clear recipes specifying time and temperature of heating. The health and nutritional value of the food as part of the patient’s diet should be considered as well as the taste and acceptance of the food. Culturally appropriate ladders should be provided, and commercial options can be offered as able. There should also be clear guidance to families on how to offer each step and for how long prior to progressing, as well as instructions for safe dosing, i.e., when the child is in their normal state of health, in the home with a parent/guardian and access to emergency medications.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

AH: Writing – original draft, Writing – review & editing. DF: Data curation, Writing – review & editing. CV: Writing – original draft, Writing – review & editing.