Prevalence of Adverse Drug Reactions: Comparing Crotalidae Immune Polyvalent Antivenoms F(ab’)₂ and F(ab) in a Galactose-alpha-1,3-galactose (alpha-gal) Endemic Area - 16/08/25

Doi : 10.1016/j.annemergmed.2025.06.618

Ari B. Filip, MD ^a, Lina Mahmood, MD ^b, Collette Tilly, MD ^b,^c, Howell R. Foster, PharmD ^a, Fawn Jackson, BA ^a, William Banner, MD, PhD ^d, Thomas A.E. Platts-Mills, MD, PhD ^e, Jeffrey Wilson, MD, PhD ^e, Pamela Schoppee Bortz, PhD ^e, Nathan Charlton, MD ^f, Joshua L. Kennedy, MD ^b,^c,^g,^⁎
^a Arkansas Poison and Drug Information Center, University of Arkansas for Medical Sciences College of Pharmacy, Little Rock, AR
^b Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR
^c Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR
^d Oklahoma Center for Poison and Drug Information, College of Pharmacy, University of Oklahoma, Oklahoma City, OK
^e Division of Allergy and Clinical Immunology, Department of Medicine, University of Virginia, Charlottesville, VA
^f Department of Emergency Medicine, University of Virginia, Charlottesville, VA
^g Arkansas Children's Research Institute, Little Rock, AR

^∗Corresponding Author.

Sous presse. Épreuves corrigées par l'auteur. Disponible en ligne depuis le Saturday 16 August 2025

Abstract

Study objectives

North American pit viper antivenoms, CroFab® and ANAVIP®, contain galactose- -1,3-galactose (α-GAL) oligosaccharide. We compared adverse drug reactions, including presumed anaphylaxis, following administration of these antivenoms and investigated biological plausibility of these antivenoms leading to anaphylaxis in α-GAL-immunoglobulin (Ig) E-sensitized individuals.

Methods

We performed 2 studies. A retrospective chart review from the Arkansas Poison Center (May 2021 to July 2023) identified adverse drug reactions and presumed anaphylaxis in patients treated with crotaline antivenom. Two allergists (JK, LM), blinded to the antivenom used, adjudicated presumed anaphylaxis cases. To assess whether antivenoms could activate basophils from α-GAL-IgE-sensitized individuals, basophil activation tests were performed on blood from 5 α-GAL-IgE-sensitized participants with a history of mammalian meat allergy. Basophil activation was assessed by %CD63 upregulation.

Results

Adverse drug reactions without presumed anaphylaxis occurred in 7 out of 171 (4.1%) Fab recipients versus 8 out of 37 (21.6%) F(ab’)₂ recipients (Δ=17.5%, 95% confidence interval [CI] [4.0 to 31.0]). Presumed anaphylaxis was observed in 3 out of 171 (1.8%) for Fab and 6/37 (16.2%) for F(ab’)₂ (Δ=14.3%, 95% CI 2.5 to 26.2). In the basophil activation tests, the mean EC₅₀ for basophil CD63 activation was 144-fold higher for Fab (mean, [standard deviation]; 647 μg/mL of antivenom [627]) compared to F(ab’)₂ (4.48 μg/mL of antivenom [2.75]).

Conclusion

We demonstrate a substantial incidence of adverse drug reactions and presumed anaphylaxis to crotaline antivenoms in an α-GAL endemic region, with F(ab’)₂ antivenom associated with more reactions than F(ab). Clinicians in α-GAL endemic regions should be cautious in the use of antivenoms, especially for patients with α-GAL allergy.

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Keywords : Galactose-alpha-1,3-galactose, Alpha-gal, Snake antivenom, Snake antivenin, Anaphylaxis

Plan

Introduction

Background

Importance

Goals of This Investigation

Methods

Study Design and Setting

Poison Center Study

Ex Vivo Analysis of Basophils

Results

Poison Center Study

Ex Vivo Analysis of Basophils

Limitations

Discussion

	Please see page XX for the Editor’s Capsule Summary of this article.
	Supervising editor: Richard C. Dart, MD, PhD. Specific detailed information about possible conflict of interest for individual editors is available at editors.
	Author contributions: AF, LM, CT, HF, WB, TPM, JK designed the study, AF, LM, FJ, JK performed data analysis and managed retrospective data. TPM, JW, PSB, NC, JK directed basic science investigations. JW and JK provided statistical support. ABF, JW, and JK drafted the manuscript. All authors substantially contributed to the manuscript’s review and revision, and JK takes responsibility for the paper as a whole.
	Data sharing statement: The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request. De-identified participant data, study protocols, and statistical analysis plans may be shared with qualified researchers to facilitate the replication of procedures or additional analyses, subject to the execution of appropriate data use agreements. Data will be available for up to 5 years following publication.
	All authors attest to meeting the four ICMJE.org authorship criteria: (1) Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; AND (2) Drafting the work or revising it critically for important intellectual content; AND (3) Final approval of the version to be published; AND (4) Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
	Funding and support: By Annals’ policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org/). The authors report that this study did not receive funding. WB compensated lectures on behalf of BTG Specialty Pharmaceuticals. Lectures were performed prior to study conception but within 3 years of study dates. JK, LM, and CT were supported by the Arkansas Biosciences Institute. All other authors report no relevant financial conflicts of interest.
	Presentation information: Data presented at North American Congress of Clinical Toxicology, September 22, 2024, Denver, CO.