High IgE Levels Predict Anaphylaxis in Low-Dose OFC for Cow’s Milk

A study identified high levels of cow’s milk- and casein-specific immunoglobulin E (IgE) as significant risk factors for a positive oral food challenge with low-dose (1 -3 mL) cow’s milk.1

Cow’s milk is a common allergy in children, affecting 2% of children < 4 years old worldwide.2 A 2020 study found that cow’s milk is the second most common food allergy in Japan, following egg allergy.3

Limited studies have reported significant risk factors for allergic symptoms during low-dose cow’s milk oral food challenges (OFCs). Previous research identified cow’s milk- and casein-specific IgE levels as key risk factors for a positive oral food challenge testing 25 mg to 200 ML of cow’s milk—but not for extremely low doses. Investigators sought to identify risk factors for allergic reactions during low-dose oral food challenges for cow’s milk at 1 – 3 mL, equivalent to 34 – 102 mg.1

“Although the [cow’s milk] dose in the current study was lower than those in prior reports, the findings are consistent with those of earlier studies,” wrote investigators, led by Yuki Sakaguchi, from the department of allergy at NHO Sagamihara National Hospital, in Japan.

The multicenter study examined the results of the first low-dose oral food challenge for cow’s milk performed at 10 hospitals in Japan between January and December 2019. Participants had eliminated cow’s milk from their diet and underwent low-dose cow’s milk oral food challenges.

In total, the study included 244 patients, with a median age of 2.5 years. Participants’ mean level of cow’s milk-specific IgE was 13.1 (interquartile range, 3.7 – 45.6) kUA/L. In the sample, 44% had a positive oral food challenge, and among those patients, 19% experienced anaphylaxis.

Compared with patients who had a negative oral food challenge, patients with a positive oral food challenge were older (3.4 vs. 1.9 years, P < .001), had greater total IgE levels (553 vs. 188 IU/mL, P < .001), increased cow’s milk sIgE levels (25.3 vs. 5.4 kUA/L, P < .001), and increased casein sIgE (25.5 vs. 5.2 kUA/L, P < .001) levels. Additionally, those who experienced anaphylaxis demonstrated greater cow’s milk-specific IgE levels (45.5 kUA/L vs 10.9 kUA/L) and casein-specific IgE levels (49.8 kUA/L vs 9.8 kUA/L).

Multivariate analyses showed that high cow’s milk- and casein-specific IgE were significant risk factors for a positive oral food challenge test (P < .001). Optimal cut-off values to predict a positive oral food challenge for cow’s milk were 5.4 kUA/L for cow’s milk-specific IgE and 7.3 kUA/L for casein-specific IgE.

When cow’s milk- or casein-specific IgE levels were 10.9 kUA/L or ≥ 11.5 kUA/L, this corresponded to a 5% likelihood of anaphylaxis. The likelihood increased to 20% when levels were ≥ 100 kUA/L.

For cow’s milk oral food challenge (OFC) outcomes, the cow’s milk-specific IgE levels corresponding to 75% and 90% positive predictive values were 106 kUA/L and 1303 kUA/L, respectively. The casein sIgE levels associated with the same positive predictive values were 144 kUA/L and 1628 kUA/L.

Other factors, such as age, male sex, anaphylaxis history, and complications of atopic dermatitis, were not found to be risk factors for allergic reactions during oral food challenges.

“In conclusion, low dose [cow’s milk] OFC in patients with high [cow’s milk] sIgE or casein sIgE levels should be carefully monitored for positive reactions,” the team wrote. “Assessing the patient's background, especially their [cow’s milk] and casein sIgE levels, to evaluate the risk of developing symptoms, including anaphylaxis, during the [cow’s milk] OFC in advance is essential.”

References

1. Sakaguchi Y, Nagakura KI, Takahashi K, et al. Low-dose oral cow's milk challenge outcome for patients on complete avoidance: A multicenter study in Japan. Pediatr Allergy Immunol. 2025;36(5):e70105. doi:10.1111/pai.70105

2. Bognanni A, Chu DK, Firmino RT, Arasi S, Waffenschmidt S, Agarwal A, Dziechciarz P, Horvath A, Jebai R, Mihara H, Roldan Y, Said M, Shamir R, Bozzola M, Bahna S, Fiocchi A, Waserman S, Schünemann HJ, Brożek JL; WAO DRACMA Guideline Group. World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) guideline update - XIII - Oral immunotherapy for CMA - Systematic review. World Allergy Organ J. 2022 Sep 8;15(9):100682. doi: 10.1016/j.waojou.2022.100682. PMID: 36185550; PMCID: PMC9474924.

3. Yamamoto-Hanada K, Pak K, Saito-Abe M, et al. Allergy and immunology in young children of Japan: The JECS cohort. World Allergy Organ J. 2020;13(11):100479. Published 2020 Nov 7. doi:10.1016/j.waojou.2020.100479