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Background: Cow’s milk (CM) is an increasingly common cause of severe allergic reactions, but there is uncertainty with respect to severity of reactions at low level CM exposure, as well as the reproducibility of reaction thresholds. Objective: To undertake an individual participant data (IPD) meta-analysis of studies reporting double-blind, placebo-controlled food challenges (DBPCFC) in CM, to determine the rate of anaphylaxis to low level exposures and the reproducibility of reaction thresholds. Methods: Systematic review and individual participant data (IPD) meta-analysis of studies reporting relevant data. Authors were contacted to provide additional data and/or clarifications as needed. Risk of bias was assessed using the National Institute for Clinical Excellence methodological checklists. Results: 34 studies were included, representing data from over 1000 participants. The cumulative ED01 and ED05 (cumulative doses causing objective symptoms in 1% and 5% of the at-risk allergic population) were 0.3 (95%CI 0.2-0.5) and 2.9 (95%CI 1.6-5.4) mg, respectively. At meta-analysis, 4.8% (95%CI 2.0-10.9%) and 4.8% (95%CI 0.7-27.1%) of individuals reacting to ≤5mg and ≤0.5mg of CM protein (respectively) had anaphylaxis (minimal heterogeneity, I 2 =0%). 110 individuals subsequently underwent a repeat DBPCFC: the intra-individual variation in reaction threshold was limited to a ½-log change in 80% (95%CI 65-89%) of participants. Two individuals initially tolerated 5mg CM protein but then reacted to this dose at a subsequent challenge, although neither had anaphylaxis. Conclusions: Around 5% of CM-allergic individuals reacting to an ED01 or ED05 exposure might have anaphylaxis to that dose. This equates to 5 and 24 anaphylaxis events per 10,000 patients exposed to an ED01 or ED05 dose respectively, in the broader CM-allergic population. The vast majority of these anaphylactic reactions would be at the more mild end of the spectrum of anaphylaxis severity, responding to single dose of epinephrine.

Background: The primary treatment for anaphylaxis is intramuscular injection of adrenaline, but sometimes the response to treatment is inadequate and continuous intravenous administration of adrenaline is required. However, there is a lack of knowledge on the frequency and optimal method of administration. We aimed to report cases in which continuous adrenaline infusion was required during oral food challenges (OFCs) at our hospital. Method: We retrospectively reviewed the medical records of the last 6 years for cases of continuous Adrenaline administration in OFC. Result: Of 8531 patients, 214 patients received intramuscular adrenaline injection, and 7 patients required continuous administration. The reason for initiation of continuous administration was cardiovascular symptoms in all patients, one of which was associated with severe upper airway obstruction. All patients received intravenous fluid bolus, and one needed endotracheal intubation. Continuous infusion was started at 0.02-0.04 µg/kg/min, and because of prolonged hypotension in two patients, the dose had to be increased. Thereafter, all patients improved, and continuous administration was discontinued at a median of 155 (IQR:145-190) minutes. All patients had no adverse events or biphasic reactions. Conclusion: Continuous adrenaline administration in OFC was successful at 0.04-0.06 µg/kg/min in treating severe anaphylaxis refractory to multiple intramuscular injections of adrenaline, and therapeutic response was achieved at a lower dose than previously recommended (0.1-1.0 µg/kg/min).

Background Cow's milk, along with hen's egg, are common causes of food allergies in children worldwide. Accidental ingestion of milk is common and often induces severe allergic reactions. Oral food challenge test (OFC) is usually performed in patients with or suspected of having a food allergy. However, the evidence of whether cow's milk OFC is useful in IgE-dependent cow's milk allergy patients to avoid total elimination is not known. Methods After setting the clinical question and outcomes, we performed a systematic review for relevant articles published from January 1, 2000 to August 31, 2019 using PubMed® and Ichushi-Web databases. Each article was then evaluated for the level of evidence. All positive results of the OFC were defined as adverse events. Results Forty articles were selected in this study. Our review revealed that cow's milk OFC was able to avoid the complete elimination of cow's milk in 66% of the patients with cow's milk allergy. We also found that adverse events occurred frequently (50.5%). Conclusions This analysis supports the recommendation of conducting cow's milk OFC to avoid complete elimination of cow's milk, however the test should be conducted with careful consideration of the patient's safety. As the methods of OFC and subjects varied among the articles selected in this study, further studies are needed to obtain higher quality evidence.

Background: An oral food challenge (OFC) is required for diagnosing food allergies; however, uncertain reactions can impair the determination of when to stop the test. We aimed to determine the associations between immediately occurring mild allergic skin signs/laryngeal symptoms and positive OFC results. Methods: We retrospectively included children (aged 6 months to 15 years) who underwent open OFC for hen’s egg (HE), cow’s milk (CM), or wheat at a single centre between May 2012 and March 2020. Participants with mild skin signs or laryngeal symptoms at OFC initiation were classified as “skin” or “laryngeal” cases, respectively. Using logistic regression, the risk of positive OFC results, in a skin or laryngeal case, was assessed using univariate and multivariate analyses. Age, sex, total target dose, and serum levels of total and food-specific immunoglobulin E were used as covariates in prediction models. Results: In total, 2954, 1126, and 850 tests for HE, CM, and wheat, respectively, were included and comprised 115 (4%) and 25 (0.9%), 92 (9%) and 24 (2%), and 7 (1.3%) and 0 (0%) skin and laryngeal cases, respectively. Children with reactions to both HE and CM had a higher risk of a positive OFC than controls (odds ratio [95% confidence interval]: 4.6 [3.3–6.4], 2.9 [2.0–4.1] and 6.5 [3.0–10.9], 4.9 [2.2–10.9], respectively). Areas under the curves of prediction models ranged from 0.61 to 0.71. Conclusions: Uncertain reactions immediately after test initiation could not robustly predict OFC results, indicating the OFC could be continued under careful observation.

Background: This study was aimed at evaluating the efficacy and safety of oral immunotherapy (OIT) in children with severe cow's milk allergy. Methods: The subjects comprised 28 children (aged 3–12 years) with allergic symptoms that were induced by ≤ 10 mL of cow's milk in an oral food challenge test (OFC). The subjects were randomly allocated to the treatment group (n = 14) and control group (n = 14); the former received rush immunotherapy for 2 weeks, followed by a gradual increase of cow's milk volume to 100 mL for 1 year, and the latter completely eliminated cow's milk for 1 year. Both groups underwent an OFC with 100 mL of cow's milk after 1 year. Results: The treatment group had significantly higher rates of a negative OFC [7/14 (50%) vs. 0/14 (0%), p 100 mL). Conclusions: The effect of immunotherapy was 50%, but the incidence of adverse events was not low. Further studies focusing on safety is necessary to standardize OIT for cow's milk allergy.