Hypersensitivity reactions due to North American pit viper antivenom administration and confirmed elevation of alpha-gal IgE

Abstract

The two current antivenom products available in the United States (US) for North American pit viper envenomation include ovine-derived Crotalidae polyvalent immune Fab (FabAV, Crofab^®) and equine-derived Crotalidae Immune (F(ab′)2, Anavip^®). Both products contain the oligosaccharide, galactose-alpha-1,3-galactose (alpha-gal), and may lead to a hypersensitivity reaction commonly referred to as alpha-gal syndrome (AGS). We report two patients receiving antivenom for pit viper envenomation who developed anaphylactic reactions and had confirmed abnormal titers of alpha-gal-specific IgE. We suggest clinicians seek a history of red meat allergy and administer AV cautiously in endemic areas of AGS.

Keywords:

• Antivenom
• alpha-gal
• allergy
• case report

Background

The two current antivenom products available in the United States (US) for North American pit viper envenomation include ovine-derived Crotalidae polyvalent immune Fab (FabAV, Crofab^®) and equine-derived Crotalidae Immune (F(ab′)2, Anavip^®). The overall incidence of adverse drug reactions (ADRs) to these products may be as low as 1.4% [1] although others have reported mild ADRs up to 56% [2]. The placebo control group in this trial had a 28% rate of ADRs although severe reactions remained rare.

A retrospective review of snakebite cases reported to our regional poison center in Oklahoma over a two-year period found a higher incidence of ADRs in both antivenom products than previously reported in post-marketing data [3].

Two cases of severe anaphylactic reactions to antivenom were reported to our regional poison center in Oklahoma. A speculative contributing factor to the regionally increased frequency in severe ADR’s to antivenom may be an immunoglobulin E (IgE)-mediated allergy to the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal), commonly referred to as alpha-gal syndrome (AGS). Chung et al. found regional differences in anaphylactic reactions to cetuximab with a frequency of reactions of 20% in the southeastern US compared to <1% in Boston and California [4]. These correlated with the regional differences in alpha-gal IgE concentrations [4]. Descriptions of life-threatening anaphylaxis to non-primate mammalian meat and other derived products, such as the monoclonal antibody cetuximab have been reported [4]. Alpha-gal syndrome may be the cause of reactions to porcine valve replacements [5] and heparin [6].

Alpha-gal reactions are attributed to tick-produced antigens, possibly from bacteria in saliva of lone star ticks (Amblyomma americanum) transferred to human hosts [7]. Lone star ticks are found in the southeastern and southcentral US, from Oklahoma to North Carolina, and reported as far north as Minnesota [8]. In lone star tick-endemic areas within the US, the incidence of alpha-gal sensitization may be as high as 15–30% [9]. The number of confirmed AGS cases has increased from 12 in 2009 to 34,000 in 2019 [5,9,10], and testing from 2017 to 2022 revealed that 30.5% of people tested (90,018) were IgE positive [11]. In vitro laboratory studies of both FabAV [12] and F(ab′)2 [13] demonstrated the presence of the alpha-gal antigen leading some to speculate that regional differences in ADR rates might be related to regional differences in rates of AGS [12]. We identified two patients receiving antivenom for pit viper envenomation who developed anaphylactic reactions, both confirmed with alpha-gal-specific IgE.

Case 1

An unidentified snake bit a 2-year-old female on the left third finger. The finger had two puncture marks with swelling, proximal blanching, and purple discoloration. Capillary refill time remained normal. Swelling progressed up her forearm. The patient was transferred to a tertiary care hospital for antivenom administration. Initial laboratory tests revealed: platelets 403 × 10³/L, INR 1.2, and fibrinogen 222 mg/dL. Six vials of FabAV were diluted in 250 mL of normal saline. After 160 mL of the infusion (exact rate not reported), she developed facial edema, urticaria, and airway involvement with bilateral wheezing. She was tachycardic with a heart rate of 170 beats per minute. A specific blood pressure value was not reported. Antivenom was promptly discontinued. She received methylprednisolone, intramuscular epinephrine, and diphenhydramine with slow resolution of symptoms. Wheezing resolved after 4 h. She was admitted to the pediatric intensive care unit for close airway observation due to the severity and duration of the reaction. The PICU team opted to neither restart FabAV nor switch to F(ab′)2. Laboratory values remained stable through hospitalization. Nadir platelets and fibrinogen were 369 × 10³/L and 206 mg/dL, respectively. The peak INR was 1.18. She was discharged home on day 4. Before discharge, alpha-gal IgE returned elevated at 13.7 kU/L (reference range ≤0.09 kU/L).

Case 2

A 47-year-old male presented to a primary access hospital following two bites to his right fifth toe from an unknown rattlesnake species. The patient initially reported blurred vision. Physical examination showed progressive swelling extending up the right calf and ecchymosis localized to the bite site. Ten vials of F(ab′)2 were administered. Upon completion, he developed pruritis and diffuse urticaria on his back, trunk, and legs, in addition to bilateral ear swelling, throat itching, and difficulty swallowing. Symptoms slowly resolved after administration of methylprednisolone, diphenhydramine, and famotidine. The urticaria and pruritus reoccurred 7 h later, in addition to oropharyngeal edema and airway involvement requiring epinephrine. Additional antivenom was not required. He was conservatively managed with extremity elevation and pain control. His blurred vision resolved. He was discharged home on day 4. Nadir platelets and fibrinogen were 171 × 10³/L and 194 mg/dL, respectively. Peak INR was 1.1. Alpha-gal IgE was elevated at 38.8 kU/L (reference range ≤0.09 kU/L).

Discussion

Alpha-gal reactions have been documented worldwide [14,15]. While individual cases report a possible association with feline flea bites [16], AGS in the US is generally related to lone star ticks [7,11]. In the US, anaphylactic reactions to cetuximab are more frequent in the southeastern US where lone star ticks are endemic and correlate with the frequency of elevated alpha-gal IgE concentrations [4]. While reports of AGS range as far north as Minnesota [8], the highest lone star tick population remains in the southeastern and southcentral US, including Oklahoma, Missouri, Arkansas, Tennessee, and North Carolina (Figure 1) [11,17].

Figure 1. Geographic distribution of suspected alpha-gal syndrome cases* per 1 million population per year—United States, 2017–2022 (from reference [11], US Centers for Disease Control and Prevention, public domain).

Of concern, either due to increased recognition or increased tick exposure, the incidence of AGS in lone-star-tick-endemic areas has increased dramatically [5,9–11]. The most common presentation of AGS is an allergic reaction to mammalian meat, particularly beef. Reactions are often severe and sometimes fatal. Reactions can be immediate or more commonly 3–6 h delayed in onset [5]. Our patients denied a prior history of meat-induced allergy following their reactions to antivenom. In contrast to other mammalian species, primate and human proteins do not include the alpha-gal moiety.

The introduction of F(ab′)2 antivenom in our local region led to a possible increased incidence of more severe reactions during infusion [18]. Whether related to observational bias for side effects of a new product, or in vitro findings of higher alpha-gal content in F(ab′)2 remains unknown [13]. Interestingly, pepsin digestion, which is used during F(ab′)2 manufacturing, might not breakdown the alpha-gal oligosaccharide [19].

A case series of patients in Laos [20] found several patients who received alpha-gal-containing antivenoms for a variety of snake envenomations, but a small number of severe reactions prevented conclusions as to whether those positive for alpha-gal IgE were more likely to have a reaction. Overall, their population had high total IgE likely due to a burden of intestinal parasitic infestation. A prior case report hypothesized FabAV may contain alpha-gal and may have caused an anaphylactic reaction [21]. A report of severe reaction to FabAV may in retrospect have been associated with AGS [22]. Ultimately, alpha-gal has been detected in FabAV [12] and more recently in F(ab′)2 [13]. Our cases are anecdotal but demonstrate the possibility that reactions to alpha-gal may have contributed to anaphylaxis following FabAV and F(ab′)2 in our two cases, both of which were confirmed with alpha-gal IgE testing.

Conclusions

Anaphylactoid reactions to antivenom occur at a low rate and generally resolve by decreasing the infusion rate and administering histamine-1 antagonists [1]. The presence of the oligosaccharide, alpha-gal, has now been established in both North American Crotalinae antivenom products approved in the U.S. We present two cases of serious reactions, both found with IgE specific for the alpha-gal moiety.

It will be important to further define the prevalence of reactions given the increasing frequency of alpha-gal allergy in the US. We suggest considering:

1. A history of allergy to mammalian meat and other mammalian-derived products be sought before administering alpha-gal-containing pharmaceuticals in lone-star-tick-endemic areas, or to individuals who have lived in these areas.

2. Maintaining caution such that antivenom is administered in hospitals prepared to manage serious ADRs and anaphylactic reactions.

3. Possible testing for alpha-gal IgE based on history and clinical scenario in patients from endemic areas with severe reactions to antivenom. Patients should be managed and counseled accordingly regarding the prevention of future tick exposures and possible future reactions to mammalian-derived products.

4. Greater availability of rapid alpha-gal IgE testing for endemic areas.

Future research and endeavors should focus on possible ways to mitigate reactions with product improvement and clear labeling of alpha-gal-containing pharmaceuticals. Risk factors should be identified, such as whether absolute alpha-gal concentration in antivenom or choice of antibody production species is associated with more severe reactions.

Ethical approval

This was considered by the University of Oklahoma Institutional Review Board and did not meet the criteria for human subjects research. This work has not been published prior.

Acknowledgments

The authors would like to thank Drs. Bo Burns and Laura Stuemky for their assistance.

Disclosure statement

Drs. Edelen, Moore, and Epperson have no conflicts of interest to declare. Dr. Banner has been a speaker for BTG manufacturer of Crofab^®.

Data availability statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Additional information

Funding

No grant support was used for this project.