Basophil reactivity, wheal size, and immunoglobulin levels distinguish degrees of cow's milk tolerance.

BACKGROUND: In our previous study about 75% of children with cow's milk allergy tolerated baked milk products, which improved their prognosis and quality of life. OBJECTIVE: We sought to identify biomarkers of varying degrees of clinical tolerance among a cohort of children with cow's milk allergy. METHODS: One hundred thirty-two subjects were initially classified as baked milk-reactive, baked milk-tolerant, or having "outgrown milk allergy" based on the results of oral food challenges. The baked milk-tolerant group was then divided into 3 groups based on the amount and degree of heat-denatured milk protein that they could tolerate. Serum was analyzed for allergen-specific IgE and IgG(4) levels, basophil reactivity was assessed in whole blood stimulated with serial 10-fold dilutions of milk protein, and skin prick tests (SPTs) were performed to commercial milk extract. Activated basophils were defined by using flow cytometry as CD63(bright)CD203c(+)CD123(+)HLA-DR(dim/-)CD41a(-)lineage(-). Data were analyzed by using the Jonckheere-Terpstra test. RESULTS: Significant differences across the 5 clinical groups were seen for median casein- and milk-specific IgE levels, casein-specific IgG(4) levels, and casein IgE/IgG(4) ratios; milk-specific to nonspecific basophil activation ratio, median basophil reactivity, and spontaneous basophil activation (CD203c expression after stimulation with RPMI); and milk SPT wheal diameters. Casein- and milk-specific IgE level, milk-specific basophil reactivity, and milk SPT wheal diameter are all significantly greater among patients with milk allergy who react to baked milk than among those who tolerate it. CONCLUSIONS: The majority of patients with milk allergy are able to tolerate some forms of baked milk in their diets. Different phenotypes of children with cow's milk allergy can be distinguished by casein- and milk-specific IgE levels, milk-specific basophil reactivity, and milk SPT mean wheal diameters. Spontaneous basophil activation is greater among patients with more severe clinical milk reactivity.

World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) guideline update - XI - Milk supplement/replacement formulas for infants and toddlers with CMA - Systematic review.

Background: Cow's milk allergy (CMA) is the most complex and common food allergy in infants. Elimination of cow's milk from the diet and replacement with a specialized formula for infants with cow's milk allergy who cannot be breastfed is an established approach to minimize the risk of severe allergic reactions while avoiding nutritional deficiencies. Given the availability of multiple options, such as extensively hydrolyzed cow's milk-based formula (eHF-CM), aminoacid formula (AAF), hydrolyzed rice formula (HRF), and soy formula (SF), there is some uncertainty regarding which formula might represent the most suitable choice with respect to health outcomes. The addition of probiotics to a specialized formula has also been proposed as a potential approach to possibly increase the benefit. We systematically reviewed specialized formulas for infants with CMA to inform the updated World Allergy Organization (WAO) DRACMA guidelines. Objective: To systematically review and synthesize the available evidence about the use of specialized formulas for the management of individuals with CMA. Methods: We searched from inception PubMed, Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and the websites of selected allergy organizations, for randomized and non-randomized trials of any language investigating specialized formulas with or without probiotics. We included all studies irrespective of the language of the original publication. The last search was conducted in January 2024. We synthesized the identified evidence quantitatively or narratively as appropriate and summarized it in the evidence profiles. We conducted this review following the PRISMA, Cochrane methods, and the GRADE approach. Results: We identified 3558 records including 14 randomized trials and 7 observational studies. Very low certainty evidence suggested that in infants with IgE-mediated CMA, eHF-CM, compared with AAF, might have higher probability of outgrowing CMA (risk ratio (RR) 2.32; risk difference (RD) 25 more per 100), while showing potentially lower probability of severe vomiting (RR 0.12, 95% CI 0.02 to 0.88; RD 23 fewer per 100, 95% CI 3 to 26) and developing food protein-induced enterocolitis syndrome (FPIES) (RR 0.15, 95% CI 0.03 to 0.82; RD 34 fewer per 100, 95% CI 7 to 39). We also found, however, that eHF-CM might be inferior to AAF in supporting a physiological growth, with respect to both weight (-5.5% from baseline, 95%CI -9.5% to -1.5%) and length (-0.7 z-score change, 95%CI -1.15 to -0.25) (very low certainty). We found similar effects for eHF-CM, compared with AAF, also in non-IgE CMA. When compared with SF, eHF-CM might favor weight gain for IgE CMA infants (0.23 z-score change, 95%CI 0.01 to 0.45), and tolerance acquisition (RR 1.86, 95%CI 1.03 to 3.37; RD 27%, 95%CI 1%-74%) for non-IgE CMA (both at very low certainty of the evidence (CoE)). The comparison of eHF-CM vs. HRF, and HRF vs. SF, showed no difference in effect (very low certainty). For IgE CMA patients, low certainty evidence suggested that adding probiotics (L. rhamnosus GG, L. casei CRL431 and B. lactis Bb-12) might increase the probability of developing CMA tolerance (RR 2.47, 95%CI 1.03 to 5.93; RD 27%, 95%CI 1%-91%), and reduce the risk of severe wheezing (RR 0.12, 95%CI 0.02 to 0.95; RD -23%, 95%CI -8% to -0.4%). However, in non-IgE CMA infants, the addition of probiotics (L. rhamnosus GG) showed no significant effect, as supported by low to very low CoE. Conclusions: Currently available studies comparing eHF-CM, AAF, HRF, and SF provide very low certainty evidence about their effects in infants with IgE-mediated and non-IgE-mediated CMA. Our review revealed several limitations in the current body of evidence, primarily arising from concerns related to the quality of studies, the limited size of the participant populations and most importantly the lack of diversity and standardization in the compared interventions. It is therefore imperative for future studies to be methodologically rigorous and investigate a broader spectrum of available interventions. We encourage clinicians and researchers to review current World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) Guidelines for suggestions on how to use milk replacement formulas in clinical practice and what additional research would be the most beneficial.

Characterizing Biphasic Food-Related Allergic Reactions Through a US Food Allergy Patient Registry.

BACKGROUND: Understanding about patient-reported biphasic food-related allergic reactions is currently sparse. OBJECTIVE: To characterize patient-reported biphasic food-related allergic reactions among a national food allergy registry. METHODS: We used two patient registry surveys established by Food Allergy Research and Education. Variables were described with proportions and 95% confidence intervals (CIs); unadjusted results were stratified by respondent type. Multivariable logistic regression evaluated the adjusted odds of reporting a biphasic reaction. RESULTS: The incidence of reported biphasic reactions was 16.4% (95% CI, 15.3-17.7). A total of 12.8% of parent or guardian respondents (95% CI, 12.5-14.3) and 21.8% of self-respondents (95% CI, 19.7-23.8) indicated a biphasic reaction during their most recent food-allergic reaction. Among respondents with a mild initial reaction, 7.4% reported a biphasic reaction, compared with 30% with a very severe initial reaction. When the initial reaction was mild, 69.6% of parent or guardian respondents (95% CI, 47.2-85.4) and 52.0% of self-respondents (95% CI, 38.0-35.7) with a biphasic reaction reported a mild secondary reaction. When the initial reaction was very severe, 36.3% of parent or guardian respondents (95% CI, 26.4-47.5) and 42.9% of self-respondents (95% CI, 31.1-55.5) with a biphasic reaction reported a very severe secondary reaction. Female sex, Black race, reaction age 5-12 and 26-66 years, initial moderate, severe, or very severe reaction, and one or more annual reactions were associated with increased odds of a biphasic reaction. CONCLUSIONS: This study characterizes the incidence of patient-reported biphasic reactions and provides valuable information on the probable severity of a biphasic food-related allergic reaction. Further research is necessary to understand the epidemiology of food-related biphasic reactions.

Mediator release assay for assessment of biological potency of German cockroach allergen extracts.

BACKGROUND: Cockroach is an important allergen in inner-city asthma. The diagnosis and treatment of cockroach allergy has been impeded by the lack of standardized cockroach extracts. OBJECTIVE: We investigated the utility of a mediator release assay based on rat basophil leukemia (RBL) cells for comparing the potency of German cockroach extracts. METHODS: RBL cells (line 2H3) transfected with human FcepsilonRI were passively sensitized with sera from subjects with cockroach allergy and stimulated with serial dilutions of 3 commercial cockroach extracts (1:10 weight/volume). In addition, the in-house prepared extract was tested in separate experiments with pooled sera that produced optimal performance in the RBL assay. N-hexosaminidase release (NHR) was used as a marker of RBL cell degranulation and was examined in relation to the intradermal skin test (ID(50)EAL) and serum cockroach-specific and total IgE levels. RESULTS: The median cockroach-specific IgE concentration in 60 subjects was 0.72 kU(A)/L (interquartile range, 0.35-2.97 kU(A)/L); 19 sera (responders) produced a minimum 10% NHR to more than 1 extract. Responders had higher median cockroach-specific IgE (7.4 vs 1.0 kU(A)/L) and total IgE (429 vs 300 kU/L) levels than nonresponders. Ranking of extract potency was consistent between the mediator release assay and the ID(50)EAL. For the in-house prepared cockroach extract, the dose-response curves were shifted according to the concentration of the extract. NHR was reproducible between different experiments by using pooled sera. CONCLUSION: The mediator release assay measures biologic potency and correlates with the ID(50)EAL. It should be further evaluated to determine whether it could be used to replace intradermal skin test titration for assessing the potency of cockroach extract.

Trends in Provider Management of Patients with Food Protein-Induced Enterocolitis Syndrome.

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy. OBJECTIVE: To better understand provider-level variation in FPIES knowledge and management. METHODS: A 23-question online survey was administered to AAAAI members during the spring and summer of 2014. RESULTS: Among 470 respondents, 64% reported "full understanding" of FPIES diagnosis/management; 78.8% reported managing 1 or more patient with FPIES; and 80.4% correctly identified an FPIES case vignette. FPIES was correctly differentiated from infantile colic or food protein-induced allergic proctocolitis by 82.5% and 71.3%, respectively. Among providers currently managing patients with FPIES, 47.5% indicated soy formula, 73.8% breast milk, and 94.5% elemental formula as appropriate substitutes in cow milk (CM)-FPIES. Skin testing is performed by 73.4%; 62.2% obtain serum food-specific IgE testing, 12.7% patch testing, 36.8% oral challenge, and 28% perform no tests. Eighty-four percent provide patients with FPIES with allergy action plans, 72.8% provide a personalized action plan, and 21% prescribe epinephrine autoinjectors. Odds of prescribing epinephrine were lower among those reporting "full understanding" of FPIES (odds ratio [OR], 0.41; 95% CI, 0.21-0.79). Academic providers had higher odds of providing an action plan (OR, 2.4; 95% CI, 1.17-4.98) and performing diagnostic oral food challenge (OR, 1.99; 95% CI, 1.99-3.25), but not of correct vignette differentiation of FPIES from other conditions, correct identification of appropriate CM-FPIES substitutes, or timing for food reintroduction. More years in practice were associated with lower odds of reporting full understanding of FPIES diagnosis/management (OR, 0.96; 95% CI, 0.94-0.99). CONCLUSIONS: Nearly one-third of respondents reported poor familiarity with FPIES. Considerable variation exists in the use of diagnostic tests, management, and choice of "safe" nutrition, indicating a strong need for FPIES practice guidelines.

Conducting an Oral Food Challenge to Peanut in an Infant.

Results from the Learning Early About Peanut trial and its follow-up study suggest that early peanut introduction in the diets of high-risk infants may prevent the development of peanut allergy. Allergy organizations around the world released a unified statement, the Consensus Communication on Early Peanut Introduction and the Prevention of Peanut Allergy in High Risk Infants, in response to results from the Learning Early About Peanut trial, which recommends early introduction of peanut into the diet of those children at greatest risk of development of peanut allergy. As a result, it is expected that practicing allergists will experience an increased demand to perform an oral food challenge (OFC) in infants. Allergists often perform OFCs; however, conducting an OFC in an infant creates unique circumstances that have not been considered in previously published OFC guideline documents. The purpose of this workgroup report is to provide guidance to practitioners regarding the proper approach for conducting a peanut challenge in an infant.

Baked Milk and Egg Diets for Milk and Egg Allergy Management.

In baked form, cow's milk and egg are less allergenic and are tolerated by most milk- and egg-allergic children. Not only may including baked milk and egg in the diets of children who are tolerant improve nutrition and promote more social inclusion but there is also evidence that inclusion may accelerate the resolution of unheated milk and egg allergy. Further research is needed on biomarkers that can predict baked milk or egg reactivity; however, data suggest casein- and ovomucoid-specific immunoglobulin E levels may be useful. Physician-supervised introduction of baked milk and egg is recommended because anaphylaxis has occurred.