Risk prediction of severe reaction to oral challenge test of cow’s milk
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.
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.
KeywordsAnaphylaxis Food allergy Multivariate logistic regression Oral food challenge Prediction model
Area under the curve
Oral food challenge
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.
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.
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 was obtained from all individual participants included in the study.
- 10.Hamasaki Y, Kohno Y, Ebisawa M, Kondo N, Nishima S, Nishimuta T, Morikawa A, Aihara Y, Akasawa A, Adachi Y, Arakawa H, Ikebe T, Ichikawa K, Inoue T, Iwata T, Urisu A, Ohya Y, Okada K, Odajima H, Katsunuma T, Kameda M, Kurihara K, Sakamoto T, Shimojo N, Suehiro Y, Tokuyama K, Nambu M, Fujisawa T, Matsui T, Matsubara T, Mayumi M, Mochizuki H, Yamaguchi K, Yoshihara S (2014) Japanese pediatric guidelines for the treatment and management of asthma 2012. Pediatr Int 56:441–450CrossRefGoogle Scholar
- 17.Muraro A, Werfel T, Hoffmann-Sommergruber K, Roberts G, Beyer K, Bindslev-Jensen C, Cardona V, Dubois A, duToit G, Eigenmann P, Fernandez Rivas M, Halken S, Hickstein L, Høst A, Knol E, Lack G, Marchisotto MJ, Niggemann B, Nwaru BI, Papadopoulos NG, Poulsen LK, Santos AF, Skypala I, Schoepfer A, van Ree R, Venter C, Worm M, Vlieg-Boerstra B, Panesar S, de Silva D, Soares-Weiser K, Sheikh A, Ballmer-Weber BK, Nilsson C, de Jong NW, Akdis CA, the EAACI Food Allergy and Anaphylaxis Guidelines Group (2014) EAACI food allergy and anaphylaxis guidelines: diagnosis and management of food allergy. Allergy 69:1008–1025CrossRefGoogle Scholar
- 22.Sampson HA (2003) Anaphylaxis and emergency treatment. Pediatrics 111:1601–1608Google Scholar
- 23.Schoemaker AA, Sprikkelman AB, Grimshaw KE, Roberts G, Grabenhenrich L, Rosenfeld L, Siegert S, Dubakiene R, Rudzeviciene O, Reche M, Fiandor A, Papadopoulos NG, Malamitsi-Puchner A, Fiocchi A, Dahdah L, Sigurdardottir ST, Clausen M, Stańczyk-Przyłuska A, Zeman K, Mills ENC, McBride D, Keil T, Beyer K (2015) Incidence and natural history of challenge-proven cow's milk allergy in European children--EuroPrevall birth cohort. Allergy 70:963–972CrossRefGoogle Scholar
- 30.van der Valk JPM, Berends I, Gerth van Wijk R, Arends NJT, van Maaren MS, de Groot H, Wichers HJ, Emons JAM, Dubois AEJ, de Jong NW (2018) Small percentage of anaphylactic reactions treated with epinephrine during food challenges in Dutch children. Ann Allergy Asthma Immunol 120:300–303CrossRefGoogle Scholar