Reproducibility of food challenge to cow's milk: Systematic review with individual participant data meta-analysis

Paul J. Turner; Nandinee Patel; Dianne E. Campbell; Hugh A. Sampson; Mayu Maeda; Toshio Katsunuma; Joost Westerhout; W. Marty Blom; Joseph L. Baumert; Geert F. Houben; Benjamin C. Remington

doi:10.1016/j.jaci.2022.04.035

Reproducibility of food challenge to cow's milk: Systematic review with individual participant data meta-analysis

Paul J. Turner^*, Nandinee Patel, Dianne E. Campbell, Hugh A. Sampson, Mayu Maeda, Toshio Katsunuma, Joost Westerhout, W. Marty Blom, Joseph L. Baumert, Geert F. Houben, Benjamin C. Remington

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

1 Citation (Scopus)

Abstract

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: We undertook an individual participant data (IPD) meta-analysis of studies reporting double-blind, placebo-controlled food challenges in CM to determine the rate of anaphylaxis to low-level exposures and the reproducibility of reaction thresholds. Methods: We performed a systematic review and IPD meta-analysis of studies reporting relevant data. Authors were contacted to provide additional data and/or clarification as needed. Risk of bias was assessed using the National Institute for Clinical Excellence methodologic checklists. Results: Thirty-four 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% confidence interval [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 ≤5 mg and ≤0.5 mg of CM protein had anaphylaxis (minimal heterogeneity, I² = 0%). Then 110 individuals underwent repeat double-blind, placebo-controlled food challenges; the intraindividual variation in reaction threshold was limited to a ½-log change in 80% (95% CI, 65-89) of participants. Two individuals initially tolerated 5 mg CM protein but then reacted to this dose at a subsequent challenge, although neither had anaphylaxis. Conclusions: About 5% of CM-allergic individuals reacting to 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. Most of these anaphylactic reactions would be mild and respond to a single dose of epinephrine.

Original language	English
Pages (from-to)	1135-1143.e8
Journal	Journal of Allergy and Clinical Immunology
Volume	150
Issue number	5
DOIs	https://doi.org/10.1016/j.jaci.2022.04.035
Publication status	Published - Nov 2022
Externally published	Yes

Keywords

Allergy
anaphylaxis
cow's milk
eliciting dose
food challenge
precautionary allergen labeling
thresholds

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10.1016/j.jaci.2022.04.035

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Turner, P. J., Patel, N., Campbell, D. E., Sampson, H. A., Maeda, M., Katsunuma, T., Westerhout, J., Blom, W. M., Baumert, J. L., Houben, G. F., & Remington, B. C. (2022). Reproducibility of food challenge to cow's milk: Systematic review with individual participant data meta-analysis. Journal of Allergy and Clinical Immunology, 150(5), 1135-1143.e8. https://doi.org/10.1016/j.jaci.2022.04.035

@article{30ef2954920d4305a1745dda99d01738,

title = "Reproducibility of food challenge to cow's milk: Systematic review with individual participant data meta-analysis",

abstract = "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: We undertook an individual participant data (IPD) meta-analysis of studies reporting double-blind, placebo-controlled food challenges in CM to determine the rate of anaphylaxis to low-level exposures and the reproducibility of reaction thresholds. Methods: We performed a systematic review and IPD meta-analysis of studies reporting relevant data. Authors were contacted to provide additional data and/or clarification as needed. Risk of bias was assessed using the National Institute for Clinical Excellence methodologic checklists. Results: Thirty-four 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% confidence interval [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 ≤5 mg and ≤0.5 mg of CM protein had anaphylaxis (minimal heterogeneity, I2 = 0%). Then 110 individuals underwent repeat double-blind, placebo-controlled food challenges; the intraindividual variation in reaction threshold was limited to a ½-log change in 80% (95% CI, 65-89) of participants. Two individuals initially tolerated 5 mg CM protein but then reacted to this dose at a subsequent challenge, although neither had anaphylaxis. Conclusions: About 5% of CM-allergic individuals reacting to 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. Most of these anaphylactic reactions would be mild and respond to a single dose of epinephrine.",

keywords = "Allergy, anaphylaxis, cow's milk, eliciting dose, food challenge, precautionary allergen labeling, thresholds",

author = "Turner, {Paul J.} and Nandinee Patel and Campbell, {Dianne E.} and Sampson, {Hugh A.} and Mayu Maeda and Toshio Katsunuma and Joost Westerhout and Blom, {W. Marty} and Baumert, {Joseph L.} and Houben, {Geert F.} and Remington, {Benjamin C.}",

note = "Funding Information: Disclosure of potential conflict of interest: P. J. Turner reports grants from UK Medical Research Council, NIHR/Imperial BRC and J. M. Charitable Foundation during the conduct of the study; and personal fees from UK Food Standards Agency, Aimmune Therapeutics, Allergenis, and Aquestive Therapeutics, outside the submitted work. D. E. Campbell is a part-time employee of DBV Technologies and reports receiving grant support from National Health and Medical Research Council of Australia and personal fees from Allergenis, Westmead Fertility Centre, and Financial Markets Foundation for Children. H. A. Sampson reports receiving consultancy fees from N-Fold, LLC, DBV Technologies, and Siolta Therapeutics, grant funding from the National Institutes of Health/National Institute of Allergy and Infectious Diseases, and royalties from Elsevier. T. Katsunuma reports lecture fees from Kyorin Pharmaceutical, Maruho, and Torii Pharmaceutical outside the submitted work. J. Westerhout, W. M. Blom, and G. F. Houben report financial support from Dutch Governmental TNO Research Cooperation Funds, Netherlands, and the Food Allergy Research and Resource Program (FARRP) of the University of Nebraska. B. C. Remington reports grants from FARRP, grants and personal fees from DBV Technologies, and travel support from ILSI Europe. The rest of the authors declare that they have no relevant conflicts of interest. Funding Information: Funded in part by a UK Medical Research Council Clinician Scientist award to P.J.T. (MR/K010468/1). N.P. and P.J.T. are supported through the National Institute for Health Research (NIHR) Biomedical Research Centre based at Imperial College Healthcare National Health Service (NHS) Trust and Imperial College London. The views expressed in this article are those of the authors and do not necessarily reflect those of the NHS, NIHR, or the Department of Health. Disclosure of potential conflict of interest: P. J. Turner reports grants from UK Medical Research Council, NIHR/Imperial BRC and J. M. Charitable Foundation during the conduct of the study; and personal fees from UK Food Standards Agency, Aimmune Therapeutics, Allergenis, and Aquestive Therapeutics, outside the submitted work. D. E. Campbell is a part-time employee of DBV Technologies and reports receiving grant support from National Health and Medical Research Council of Australia and personal fees from Allergenis, Westmead Fertility Centre, and Financial Markets Foundation for Children. H. A. Sampson reports receiving consultancy fees from N-Fold, LLC, DBV Technologies, and Siolta Therapeutics, grant funding from the National Institutes of Health/National Institute of Allergy and Infectious Diseases, and royalties from Elsevier. T. Katsunuma reports lecture fees from Kyorin Pharmaceutical, Maruho, and Torii Pharmaceutical outside the submitted work. J. Westerhout, W. M. Blom, and G. F. Houben report financial support from Dutch Governmental TNO Research Cooperation Funds, Netherlands, and the Food Allergy Research and Resource Program (FARRP) of the University of Nebraska. B. C. Remington reports grants from FARRP, grants and personal fees from DBV Technologies, and travel support from ILSI Europe. The rest of the authors declare that they have no relevant conflicts of interest. Funding Information: Funded in part by a UK Medical Research Council Clinician Scientist award to P.J.T. (MR/K010468/1). N.P. and P.J.T. are supported through the National Institute for Health Research ( NIHR ) Biomedical Research Centre based at Imperial College Healthcare National Health Service ( NHS ) Trust and Imperial College London . The views expressed in this article are those of the authors and do not necessarily reflect those of the NHS, NIHR, or the Department of Health. Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = nov,

doi = "10.1016/j.jaci.2022.04.035",

language = "English",

volume = "150",

pages = "1135--1143.e8",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Mosby Inc.",

number = "5",

}

Turner, PJ, Patel, N, Campbell, DE, Sampson, HA, Maeda, M, Katsunuma, T, Westerhout, J, Blom, WM, Baumert, JL, Houben, GF & Remington, BC 2022, 'Reproducibility of food challenge to cow's milk: Systematic review with individual participant data meta-analysis', Journal of Allergy and Clinical Immunology, vol. 150, no. 5, pp. 1135-1143.e8. https://doi.org/10.1016/j.jaci.2022.04.035

TY - JOUR

T1 - Reproducibility of food challenge to cow's milk

T2 - Systematic review with individual participant data meta-analysis

AU - Turner, Paul J.

AU - Patel, Nandinee

AU - Campbell, Dianne E.

AU - Sampson, Hugh A.

AU - Maeda, Mayu

AU - Katsunuma, Toshio

AU - Westerhout, Joost

AU - Blom, W. Marty

AU - Baumert, Joseph L.

AU - Houben, Geert F.

AU - Remington, Benjamin C.

N1 - Funding Information: Disclosure of potential conflict of interest: P. J. Turner reports grants from UK Medical Research Council, NIHR/Imperial BRC and J. M. Charitable Foundation during the conduct of the study; and personal fees from UK Food Standards Agency, Aimmune Therapeutics, Allergenis, and Aquestive Therapeutics, outside the submitted work. D. E. Campbell is a part-time employee of DBV Technologies and reports receiving grant support from National Health and Medical Research Council of Australia and personal fees from Allergenis, Westmead Fertility Centre, and Financial Markets Foundation for Children. H. A. Sampson reports receiving consultancy fees from N-Fold, LLC, DBV Technologies, and Siolta Therapeutics, grant funding from the National Institutes of Health/National Institute of Allergy and Infectious Diseases, and royalties from Elsevier. T. Katsunuma reports lecture fees from Kyorin Pharmaceutical, Maruho, and Torii Pharmaceutical outside the submitted work. J. Westerhout, W. M. Blom, and G. F. Houben report financial support from Dutch Governmental TNO Research Cooperation Funds, Netherlands, and the Food Allergy Research and Resource Program (FARRP) of the University of Nebraska. B. C. Remington reports grants from FARRP, grants and personal fees from DBV Technologies, and travel support from ILSI Europe. The rest of the authors declare that they have no relevant conflicts of interest. Funding Information: Funded in part by a UK Medical Research Council Clinician Scientist award to P.J.T. (MR/K010468/1). N.P. and P.J.T. are supported through the National Institute for Health Research (NIHR) Biomedical Research Centre based at Imperial College Healthcare National Health Service (NHS) Trust and Imperial College London. The views expressed in this article are those of the authors and do not necessarily reflect those of the NHS, NIHR, or the Department of Health. Disclosure of potential conflict of interest: P. J. Turner reports grants from UK Medical Research Council, NIHR/Imperial BRC and J. M. Charitable Foundation during the conduct of the study; and personal fees from UK Food Standards Agency, Aimmune Therapeutics, Allergenis, and Aquestive Therapeutics, outside the submitted work. D. E. Campbell is a part-time employee of DBV Technologies and reports receiving grant support from National Health and Medical Research Council of Australia and personal fees from Allergenis, Westmead Fertility Centre, and Financial Markets Foundation for Children. H. A. Sampson reports receiving consultancy fees from N-Fold, LLC, DBV Technologies, and Siolta Therapeutics, grant funding from the National Institutes of Health/National Institute of Allergy and Infectious Diseases, and royalties from Elsevier. T. Katsunuma reports lecture fees from Kyorin Pharmaceutical, Maruho, and Torii Pharmaceutical outside the submitted work. J. Westerhout, W. M. Blom, and G. F. Houben report financial support from Dutch Governmental TNO Research Cooperation Funds, Netherlands, and the Food Allergy Research and Resource Program (FARRP) of the University of Nebraska. B. C. Remington reports grants from FARRP, grants and personal fees from DBV Technologies, and travel support from ILSI Europe. The rest of the authors declare that they have no relevant conflicts of interest. Funding Information: Funded in part by a UK Medical Research Council Clinician Scientist award to P.J.T. (MR/K010468/1). N.P. and P.J.T. are supported through the National Institute for Health Research ( NIHR ) Biomedical Research Centre based at Imperial College Healthcare National Health Service ( NHS ) Trust and Imperial College London . The views expressed in this article are those of the authors and do not necessarily reflect those of the NHS, NIHR, or the Department of Health. Publisher Copyright: © 2022 The Authors

PY - 2022/11

Y1 - 2022/11

N2 - 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: We undertook an individual participant data (IPD) meta-analysis of studies reporting double-blind, placebo-controlled food challenges in CM to determine the rate of anaphylaxis to low-level exposures and the reproducibility of reaction thresholds. Methods: We performed a systematic review and IPD meta-analysis of studies reporting relevant data. Authors were contacted to provide additional data and/or clarification as needed. Risk of bias was assessed using the National Institute for Clinical Excellence methodologic checklists. Results: Thirty-four 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% confidence interval [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 ≤5 mg and ≤0.5 mg of CM protein had anaphylaxis (minimal heterogeneity, I2 = 0%). Then 110 individuals underwent repeat double-blind, placebo-controlled food challenges; the intraindividual variation in reaction threshold was limited to a ½-log change in 80% (95% CI, 65-89) of participants. Two individuals initially tolerated 5 mg CM protein but then reacted to this dose at a subsequent challenge, although neither had anaphylaxis. Conclusions: About 5% of CM-allergic individuals reacting to 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. Most of these anaphylactic reactions would be mild and respond to a single dose of epinephrine.

AB - 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: We undertook an individual participant data (IPD) meta-analysis of studies reporting double-blind, placebo-controlled food challenges in CM to determine the rate of anaphylaxis to low-level exposures and the reproducibility of reaction thresholds. Methods: We performed a systematic review and IPD meta-analysis of studies reporting relevant data. Authors were contacted to provide additional data and/or clarification as needed. Risk of bias was assessed using the National Institute for Clinical Excellence methodologic checklists. Results: Thirty-four 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% confidence interval [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 ≤5 mg and ≤0.5 mg of CM protein had anaphylaxis (minimal heterogeneity, I2 = 0%). Then 110 individuals underwent repeat double-blind, placebo-controlled food challenges; the intraindividual variation in reaction threshold was limited to a ½-log change in 80% (95% CI, 65-89) of participants. Two individuals initially tolerated 5 mg CM protein but then reacted to this dose at a subsequent challenge, although neither had anaphylaxis. Conclusions: About 5% of CM-allergic individuals reacting to 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. Most of these anaphylactic reactions would be mild and respond to a single dose of epinephrine.

KW - Allergy

KW - anaphylaxis

KW - cow's milk

KW - eliciting dose

KW - food challenge

KW - precautionary allergen labeling

KW - thresholds

UR - http://www.scopus.com/inward/record.url?scp=85133389656&partnerID=8YFLogxK

U2 - 10.1016/j.jaci.2022.04.035

DO - 10.1016/j.jaci.2022.04.035

M3 - Article

C2 - 35688284

AN - SCOPUS:85133389656

SN - 0091-6749

VL - 150

SP - 1135-1143.e8

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 5

ER -

Reproducibility of food challenge to cow's milk: Systematic review with individual participant data meta-analysis

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