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Cow's milk allergy (CMA) is one of the most common presentations of food allergy in early childhood. Management of CMA involves individualized avoidance of cow's milk and other mammalian milk and foods containing these. Optimal elimination of cow's milk avoidance includes: label reading; information about safe and nutritious substitute foods; appropriate choice of infant formula or a plant-based food; establishing tolerance to baked milk and monitoring nutritional intake and growth. Substitute formulas are divided into soy formula (not hydrolyzed), milk-based extensively hydrolyzed formulas, rice based extensive, and partially hydrolyzed formulas and amino acid-based formulas. The use of other mammalian milks is not recommended for the management of cow's milk allergy due to a high level of cross-reactivity and nutritional concerns. For toddlers who are eating well, children, and adults, a suitable plant-based beverage may be a suitable alternative to a specialized formula, following careful nutritional considerations. Families need to be instructed on finding suitable nutritious foods and how to prepare suitable meals at home. Individuals with CMA also need to know how to identify and treat acute severe reactions.

Background: Cow's milk allergy (CMA) is the most common food allergy in infants. The replacement with specialized formulas is an established clinical approach to ensure adequate growth and minimize the risk of severe allergic reactions when breastfeeding is not possible. Still, given the availability of multiple options, such as extensively hydrolyzed cow's milk protein formula (eHF-CM), amino acid formula (AAF), hydrolyzed rice formula (HRF) and soy formulas (SF), there is some uncertainty as to the most suitable choice with respect to health outcomes. Furthermore, the addition of probiotics to a formula has been proposed as a potential approach to maximize benefit. Objective: These evidence-based guidelines from the World Allergy Organization (WAO) intend to support patients, clinicians, and others in decisions about the use of milk specialized formulas, with and without probiotics, for individuals with CMA. Methods: WAO formed a multidisciplinary guideline panel balanced to include the views of all stakeholders and to minimize potential biases from competing interests. The McMaster University GRADE Centre supported the guideline-development process, including updating or performing systematic evidence reviews. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used, including GRADE Evidence-to-Decision frameworks, which were subject to review by stakeholders. Results: After reviewing the summarized evidence and thoroughly discussing the different management options, the WAO guideline panel suggests: a) using an extensively hydrolyzed (cow's milk) formula or a hydrolyzed rice formula as the first option for managing infants with immunoglobulin E (IgE) and non-IgE-mediated CMA who are not being breastfed. An amino-acid formula or a soy formula could be regarded as second and third options respectively; b) using either a formula without a probiotic or a casein-based extensively hydrolyzed formula containing Lacticaseibacillus rhamnosus GG (LGG) for infants with either IgE or non-IgE-mediated CMA.The issued recommendations are labeled as “conditional” following the GRADE approach due to the very low certainty about the health effects based on the available evidence. Conclusions: If breastfeeding is not available, clinicians, patients, and their family members might want to discuss all the potential desirable and undesirable consequences of each formula in infants with CMA, integrating them with the patients' and caregivers’ values and preferences, local availability, and cost, before deciding on a treatment option. We also suggest what research is needed to determine with greater certainty which formulas are likely to be the most beneficial, cost-effective, and equitable.

Cow's milk allergy is rare in exclusively breastfed infants. To support the continuation of breastfeeding an infant after diagnosis with a cow's milk allergy, it is critical to examine the evidence for and against any form of cow's milk elimination diet for lactating mothers. In this narrative review, we highlight the lack of high-quality evidence, hence subsequent controversy, regarding whether the minuscule quantities of cow's milk proteins detectable in human milk cause infant cow's milk allergy symptoms. Current clinical practice recommendations advise a 2–4 week trial of maternal cow's milk dietary elimination for: a) IgE-mediated cow's milk allergy only if the infant is symptomatic on breastfeeding alone; b) non-IgE-mediated associated symptoms only if the history and examination strongly suggest cow's milk allergy; and c) infants with moderate to severe eczema/atopic dermatitis, unresponsive to topical steroids and sensitized to cow's milk protein. There should be a clear plan for home reintroduction of cow's milk into the maternal diet for a period of 1 week to determine that the cow's milk elimination is responsible for resolution of symptoms, and then subsequent reoccurrence of infant symptoms upon maternal cow's milk reintroduction. The evidence base to support the use of maternal cow's milk avoidance for the treatment of a breastfed infant with cow's milk allergy is of limited strength due to a lack of high-quality, adequately powered, randomised controlled trials. It is important to consider the consequences of maternal cow's milk avoidance on reducing immune enhancing factors in breast milk, as well as the potential nutritional and quality of life impacts on the mother. Referral to a dietitian is advised for dietary education, along with calcium and vitamin D supplementation according to local recommendations, and a maternal substitute milk should be advised. However, for most breastfed infants with cow's milk allergy maternal cow's milk dietary elimination will not be required, and active support of the mother to continue breastfeeding is essential.

Background: Allergic diseases are increasing globally and are a significant public health challenge, especially in children. Cow's milk allergy (CMA) is one of the most common food allergies in early childhood. When CMA is diagnosed and exclusive breastfeeding is not possible, current guidelines recommend extensively hydrolyzed formulas (eHF) or amino acid-based formulas (AAF), depending on the diagnosis and severity of symptoms. Hydrolyzed rice formulas (HRF) are considered an alternative to eHF and AAF where available. Objectives & methods: We aimed to understand how HRF are being used and their position in the management of CMA, and to generate consensus on indications for use. Two virtual roundtables of international healthcare experts in pediatric food allergy focused on HRF were convened in May and October 2021. Experts provided multiple perspectives due to different specialties, locations, healthcare settings, and availability of HRF. Following discussion of international CMA guidelines and HRF use, identification of challenges along the diagnosis and treatment pathway, and translation of guidelines into clinical practice, an expert consensus on the use of HRF for CMA was developed. This involved repeated voting followed by statement amendment to reach 100% agreement. This publication summarizes insights from these meetings. Results: There was 100% agreement on all 8 statements: (1) While breastmilk is the best source of nutrition for infants with CMA, when breastfeeding is not possible, a hypoallergenic formula can be used; (2) Per definition, a HRF is cow's milk protein-free; (3) A minority of infants with immunoglobulin (Ig)E-mediated CMA react to eHF due to residual cow's milk protein; (4) More infants with non-IgE-mediated CMA than IgE-mediated CMA react to eHF likely due to residual cow's milk protein; (5) When a diagnostic elimination diet is indicated, HRF can be used; (6) A HRF can be recommended as a first-line option for CMA, where available, as outlined in the Diagnosis and Rationale for Action against Cow's Milk Allergy guidelines; (7) HRFs have proven hypoallergenicity and are suitable for the dietary management of CMA; (8) HRFs have been shown to support growth in infants with CMA, similar to other hypoallergenic formulas. Participants recommend healthcare professionals take these statements as guidance to use HRF in clinical practice. Based on efficacy and growth evidence, the experts found HRF a suitable option for the dietary management of CMA. Conclusion: HRF can be recommended as a first-line alternative to cow's milk-based eHF or AAF, where available, in the dietary management of CMA.

Background: Allergy to cow's milk is the most common food allergy in infants and it is usually outgrown by 5 years of age. In some individuals it persists beyond early childhood. Oral immunotherapy (OIT, oral desensitization, specific oral tolerance induction) has been proposed as a promising therapeutic strategy for persistent IgE-mediated cow's milk allergy. We previously published the systematic review of OIT for cow's milk allergy (CMA) in 2010 as part of the World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) Guidelines. Objective: To systematically synthesize the currently available evidence about OIT for IgE-mediated CMA and to inform the updated 2022 WAO guidelines. Methods: We searched the electronic databases including PubMed, Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and the websites of selected allergy organizations. We included all studies irrespective of the language of the original publication. The last search was conducted in February 2021. We registered the protocol on Open Science Framework (10.17605/OSF.IO/AH2DT). Results: We identified 2147 unique records published between 2010 and 2021, including 13 randomized trials and 109 observational studies addressing cow's milk OIT. We found low-certainty evidence that OIT with unheated cow's milk, compared to elimination diet alone, increased the likelihood of being able to consume ≥150 ml of cow's milk in controlled settings (risk ratio (RR): 12.3, 95% CI: 5.9 to 26.0; risk difference (RD): 25 more per 100, 95% CI 11 to 56) as well as accidently ingest a small amount (≥5 ml) of cow's milk (RR: 8.7, 95% CI: 4.7 to 16.1; RD: 25 more per 100, 95% CI 12 to 50). However, 2–8 weeks after discontinuation of a successful OIT, tolerance of cow's milk persisted in only 36% (range: 20%–91%) of patients. OIT increased the frequency of anaphylaxis (rate ratio: 60.0, 95% CI 15 to 244; rate difference 5 more anaphylactic reactions per 1 person per year, 95% CI: 4 to 6; moderate evidence) and the frequency of epinephrine use (rate ratio: 35.2, 95% CI: 9 to 136.5; rate difference 268 more events per 100 person-years, 95% CI: 203 to 333; high certainty). OIT also increased the risk of gastrointestinal symptoms (RR 6.9, 95% CI 1.6–30.9; RD 28 more per 100, CI 3 to 100) and respiratory symptoms (RR 49.0, 95% CI 3.12–770.6; RD 77 more per 100, CI 62 to 92), compared with avoidance diet alone. Single-arm observational studies showed that on average 6.9% of OIT patients (95% CI: 3.8%–10%) developed eosinophilic esophagitis (very low certainty evidence). We found 1 trial and 2 small case series of OIT with baked milk. Conclusions: Moderate certainty evidence shows that OIT with unheated cow's milk in patients with IgE-mediated CMA is associated with an increased probability of being able to drink milk and, at the same time, an increased risk of serious adverse effects.

Background: The prevalence of cow's milk allergy (CMA) is approximately 2–4.5% in infants and less than 0.5% in adults. Most children outgrow cow's milk allergy in early childhood, particularly that to the baked milk products. Immunotherapy with unheated cow's milk has been used as a treatment option for those who have not yet outgrown CMA, but the benefits must be balanced with the adverse effects. Objective: These evidence-based guidelines from the World Allergy Organization (WAO) intend to support patients, clinicians, and others in decisions about the use of oral and epicutaneous immunotherapy for the treatment of IgE-mediated CMA. Methods: WAO formed a multidisciplinary guideline panel balanced to include the views of all stakeholders and to minimize potential biases from competing interests. The McMaster University GRADE Centre supported the guideline-development process, including updating or performing systematic evidence reviews. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used, including GRADE Evidence-to-Decision frameworks, which were subject to public comment. Results: After a careful review of the summarized evidence and thorough discussions the WAO guideline panel suggests: a) using oral immunotherapy with unheated cow's milk in those individuals with confirmed IgE-mediated CMA who value the ability to consume controlled quantities of milk more than avoiding the large adverse effects of therapy, b) not using oral immunotherapy with unheated cow's milk in those who value avoiding large adverse effects of therapy more than the ability to consume controlled quantities of milk, c) using omalizumab in those starting oral immunotherapy with unheated cow's milk, d) not using oral immunotherapy with baked cow's milk in those who do not tolerate both unheated and baked milk, and e) not using epicutaneous immunotherapy outside of a research setting. The recommendations are labeled “conditional” due to the low certainty about the health effects based on the available evidence. Conclusions: Clinicians, patients, and their family members might want to discuss all the potential desirable and undesirable effects of oral immunotherapy for IgE-mediated CMA and integrate them with the patients' values and preferences before deciding on a treatment option. More robust research is needed to determine with greater certainty which interventions are likely to be the most beneficial with the least harms, and to develop safer, low-cost, and equitable treatments.

Since the World Allergy Organization (WAO) Diagnosis and Rationale against Cow's Milk Allergy (DRACMA) Guidelines were published 10 years ago, new evidence has accumulated about the diagnosis, therapy, and specific immunotherapy for cow's milk allergy (CMA). For this reason, WAO has felt the need to update the guidelines.We introduce here this update. The new DRACMA guidelines aim to comprehensively address the guidance on diagnosis and therapy of both IgE non-IgE-mediated forms of cow's milk allergy in children and adults. They will be divided into 18 chapters, each of which will be dedicated to an aspect. The focus will be on the meta-analyzes and recommendations that will be expressed for the 3 most relevant clinical aspects: (a) the diagnostic identification of the condition; (b) the choice of the replacement formula in case of CMA in infancy when the mother is not able to breastfeed, and (c) the use of specific immunotherapy for cow's milk protein allergy.

Abstract Background In 2010, the diagnosis and treatment of IgE-mediated CMA were systematized in a GRADE guideline. Objectives & methods After 6 years, the state of the knowledge in diagnosis and treatment of CMA has largely evolved. We summarize here the main advances, and exemplify indicating some specific points: studies aimed at better knowledge of the effects of breastfeeding and the production of new special formulae intended for the treatment of CMA. The literature (PubMed/MEDLINE) was searched using the following algorithms: (1) [milk allergy] AND diagnosis; (2) [milk allergy] AND [formul*] OR [breast*], setting the search engine [6-years] time and [human] limits. The authors drew on their collective clinical experience to restrict retrieved studies to those of relevance to a pediatric allergy practice. Results Several clinical studies did address the possibility to diagnose CMA using new tools in vitro and in vivo, or to diagnose it without any evaluation of sensitization. Some studies also addressed the clinical role of formulae based on milk hydrolysates, soy, or rice hydrolysates in the treatment of CMA. Many studies have elucidated the effects of selective nutrients in breastfed infants on their immunologic and neurologic characteristics. Conclusions Evidence-based diagnostic criteria should be identified for non-IgE-mediated CMA. Debate is ongoing about the best substitute for infants with CMA. In particular, Hydrolyzed Rice Formulae have been widely assessed in the last six years. In the substitute choice, clinicians should be aware of recent studies that can modify the interpretation of the current recommendations. New systematic reviews and metanalyses are needed to confirm or modify the current DRACMA recommendations.