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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).