Anaphylaxis occurs in about 5% of allergic reactions to low doses of cow’s milk

Anaphylaxis may occur to low-level cow’s milk exposure among approximately 5% of allergic individuals reacting to these doses, according to a study in The Journal of Allergy and Clinical Immunology.

Most of these anaphylactic reactions would be mild and treatable with a single dose of epinephrine, Paul J. Turner, FRCPCH, PhD, of the National Heart & Lung Institute at Imperial College London, and colleagues wrote.

To determine the rate of anaphylaxis to love-level exposures and the reproducibility of reaction thresholds, the researchers reviewed 34 studies describing 1,002 double-blind, placebo-controlled food challenges (DBPCFCs) to cow’s milk (CM) published between January 1984 and December 2021.

Overall, these challenges established cumulative eliciting doses for the amount of CM protein predicted to cause objective symptoms in 1% of the CM-allergic population (ED₀₁) of 0.3 mg (95% CI, 0.2-0.5) and in 5% of the CM-allergic population (ED₀₅) of 2.9 mg (95% CI, 1.6-5.4).

Researchers then assessed the rate of anaphylaxis to low level exposures based on the upper 95% CIs of ED₀₁ (0.5 mg) and ED₀₅ (5 mg).

In 14 of the studies, 105 individuals reacted to 5 mg or less of CM protein, with 4.8% (95% CI, 2%-10.9%) of them having an anaphylactic reaction. In three other studies, 4.8% (95% CI, 0.7%-27.1%) of the reactions to 0.5 mg or less of CM protein were anaphylactic.

Researchers then tested the reproducibility of these reactions thresholds using data from five interventional studies that included participants who had a repeat food challenge for CM between 5 and 12 months after an initial baseline challenge. With a median cumulative reaction threshold of 144 mg of CM protein (interquartile range, 44 mg-444 mg), they had an overall anaphylaxis rate of 14.5%.

During repeat challenges, 80% of participants reacted to within ± one-half log-increment of the initial challenge, which the researchers said was equivalent to being within one dosing interval. Also, the individuals who had reactions to lower doses during their first DBPCFC were more likely to have reactions to higher doses during the repeat challenge with a ± one-half-log increase or greater in reaction threshold.

The researchers noted four individuals who had reactions to 5 mg or less during their initial challenge then reacted to 5 mg or greater during a later challenge. Also, there were two individuals who reacted to 5 mg or less during a later challenge even though they had initially tolerated that dose.

None of the individuals who initially tolerated an ED₀₅ level of exposure had anaphylaxis to this same dose or less during a later challenge.

To assess incidence of recurrent anaphylaxis, researchers evaluated three studies involving repeat DBPCFCs among 33 participants with at least one anaphylaxis reaction, including four who had anaphylaxis during both challenges, with reactions to the same threshold in both instances.

The researchers said that the anaphylaxis occurrence was not predictable; however, 17 of these patients (52%; 95% CI, 34%-69%) had anaphylaxis at the first but not the second challenge to the same or a higher level of CM exposure.

Overall, the researchers determined an overall risk for anaphylaxis in the broader population of people with CM allergy of five events per 10,000 patients exposed to an ED₀₁ dose and 24 events per 10,000 patients exposed to an ED₀₅ dose, equating to 2.9 mg CM protein or 0.1 mL of fresh milk. Most anaphylactic reactions would be mild and responsive to a single dose of epinephrine, the researchers continued.

Further, fewer than 5% of individuals would react to a sub-ED05 level having previously tolerated it, and individuals that do react would be “very unlikely” to have anaphylaxis, the researchers wrote.

Expressing confidence in their results, the researchers noted the minimal heterogeneity they observed at meta-analysis and when comparing clearly defined criteria for lowest observed adverse effect level and dose-limiting symptoms.

Also, the researchers said these findings support the use of eliciting doses to inform the need for precautionary allergy labeling after food businesses conduct formal allergen risk assessments. These findings could be used to inform strategies for establishing evidence-based approaches to allergen management as well, the researchers continued.