European Journal of Pediatrics

, Volume 178, Issue 2, pp 181–188 | Cite as

Risk prediction of severe reaction to oral challenge test of cow’s milk

  • Takahiro Kawahara
  • Junichiro TezukaEmail author
  • Takahito Ninomiya
  • Satoshi Honjo
  • Natsuko Masumoto
  • Makiko Nanishi
  • Hideki Nakayama
  • Shouichi Ohga
Original Article


Cow’s milk is one of the most common food allergens among children. Oral food challenge tests determine the threshold dose of allergens, but have not been standardized. To reduce the severe reactions, we developed a practical model of the test. We studied 111 high-risk patients who underwent a first milk oral food challenge on the risk-stratified dose between 2011 and 2017 for predicting the severe reaction risk. Severe reactions were defined as showing > 3 of Sampson’s classification grade. Twenty-eight patients (25%) showed severe reactions without death. Prior to oral food challenge, severe reaction patients experienced milk avoidance (71% vs. 45%, p = 0.02) or bronchial asthma (61% vs. 28%, p = 0.003) more frequently and showed higher milk-specific IgE levels (median 28.3 vs. 7.7 UA/mL, p < 0.0001) than non-severe reaction patients. Multivariate logistic regression analyses established a formula including severe reaction-associated factors; increased levels of milk-specific IgE (odds ratio 11.61, p = 0.001), milk avoidance (odds ratio 3.88, p = 0.02), and bronchial asthma (odds ratio 3.75, p = 0.02). This model had 86% sensitivity and 56% specificity (cut-off 0.25) for risk. Five patients with < 25% probability developed severe reactions, which started in > 3 grade dyspnea up to 20 mL of challenge.

Conclusion: This model could effectively reduce the severe reaction development on the first milk oral food challenge test according to the individual needs.

What is Known:

Higher levels of milk-specific IgE values, bronchial asthma, and complete milk avoidance are independent risk factors of severe reactions during the cow’s milk oral food challenge.

What is New:

Statistical analyses of our milk oral food challenge records for 111 patients helped us develop a model formula predicting severe reactions at the first test with high specificity and sensitivity.

This simple risk-stratified protocol is useful for minimizing the adverse events in the first milk challenge.


Anaphylaxis Food allergy Multivariate logistic regression Oral food challenge Prediction model 



Area under the curve


Cow’s milk


Immunoglobulin E


Oral food challenge


Odds ratio


Receiver operating characteristics



We thank all members of the specialized team for supporting the completion of the OFC tests at Fukuoka Higashi Medical Center and Fukuoka Children’s Hospital. We also thank Dr. Brian Quinn (Editor-in-Chief. Japan Medical Communication) for editing the manuscript.

Authors’ contributions

Takahiro Kawahara, Junichiro Tezuka, and Shouichi Ohga were the principal investigators taking primary responsibility for the paper. Natsuko Masumoto and Makiko Nanishi completed the survey questionnaires, made the clinical diagnosis, and confirmed the clinical and laboratory data. Takahito Ninomiya and Hideki Nakayama supported the clinical study with helpful discussions. Satoshi Honjo supported the statistical analysis. Takahiro Kawahara and Junichiro Tezuka wrote the first draft of the manuscript.

Funding information

This work was supported in part by a Grant-in Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by a grant from the Ministry of Health, Labor and Welfare of Japan.

Compliance with ethical standards

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This investigation was approved by the Institutional Review Board at the institutions (Registration code: H29-clini2). This article does not contain any studies with animals performed by any of the authors.

Conflict of interest

The authors declare that they have no conflict of interest.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

431_2018_3274_MOESM1_ESM.pptx (958 kb)
ESM 1 (PPTX 957 kb)
431_2018_3274_MOESM2_ESM.docx (15 kb)
ESM 2 (DOCX 14 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Takahiro Kawahara
    • 1
    • 2
  • Junichiro Tezuka
    • 3
    Email author
  • Takahito Ninomiya
    • 4
  • Satoshi Honjo
    • 4
  • Natsuko Masumoto
    • 2
  • Makiko Nanishi
    • 2
  • Hideki Nakayama
    • 5
  • Shouichi Ohga
    • 1
  1. 1.Department of Pediatrics, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
  2. 2.Division of PediatricsNational Hospital Organization Fukuoka Higashi Medical CenterKoga cityJapan
  3. 3.Division of Allergy and PulmonologyFukuoka Children’s HospitalFukuokaJapan
  4. 4.Division of PediatricsNational Hospital Organization Fukuoka HospitalFukuokaJapan
  5. 5.Division of PediatricsNational Hospital Organization Kyushu Cancer CenterFukuokaJapan

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