Repeat antivenom administration following crotalidae immune F(ab’)2 antivenom in Agkistrodon species: a case series

Abstract Crotalidae immune F(ab’)2 [equine] was approved for the treatment of North American rattlesnake envenomation in 2015 and Agkistrodon envenomation in 2021 after a phase 3 trial demonstrated lower rates of late hemotoxicity compared to crotalidae polyvalent immune fab-ovine (Fab) in a population of primarily rattlesnake envenomations. Currently, there are limited data on the use of this new antivenom in controlling tissue damage associated with Agkistrodon envenomations. We describe four cases of Agkistrodon contortrix envenomation in which edema continued to progress despite standard doses of F(ab’)2, necessitating administration of additional antivenom. In three cases, control was achieved only after a switch to Fab. As F(ab’)2 use in envenomations by the primarily cytotoxic Agkistrodons increases, further research is needed to evaluate its ability to control tissue damage.


Introduction
After production of the older whole IgG antivenom ceased, crotalidae polyvalent immune fab-ovine (Fab) [CroFab ® , BTG International Inc.] was the only available treatment for North American pit viper envenomation for over a decade.In 2015, the FDA approved crotalidae immune F(ab') 2 [Anavip®, Rare Disease Therapeutics Inc.] for the treatment of rattlesnake envenomation after a clinical trial demonstrated significantly lower rates of late coagulopathy compared to Fab [1].However, this trial did not evaluate for control of tissue damage [2].A later analysis of only 21 Agkistrodon contortrix envenomations in the trial showed no difference in controlling tissue damage between the two antivenoms [3].Subsequently in 2021, the FDA expanded F(ab') 2 indications to all North American pit viper envenomations [4].Unlike rattlesnakes, Agkistrodons rarely cause clinically significant hemotoxicity, making cytotoxic venom effects the primary concern [5,6].There are limited data on the ability of F(ab') 2 to control cytotoxicity from Agkistrodon envenomations.
We describe four cases of Agkistrodon contortrix envenomation treated with F(ab') 2 who received additional antivenom beyond the manufacturer's recommended dose to obtain control of cytotoxic tissue damage.

Case 1
A 13-year-old male was bitten on the right middle finger by a copperhead (Agkistrodon contortrix) while camping.He developed severe pain and swelling into the mid-hand and received ten vials of F(ab') 2 within three hours of envenomation.
His edema progressed to the elbow and wrist flexion/extension was moderately reduced by the time of his transfer to a pediatric tertiary care facility.A medical toxicologist evaluated patient upon arrival and re-bolused four vials of Fab six hours post-envenomation.The change in antivenom was necessitated by the formulary of the second hospital.
Swelling progression ceased after the Fab dose, and subsequent maintenance doses of Fab were deferred.Laboratory parameters remained normal, and the patient was discharged the following day.One week later, the patient had no lingering tissue damage or joint limitations.

Case 2
A 28-year-old male attempted to pick up an Agkistrodon contortrix who envenomated him on the second digit of his left hand.He received ten vials of F(ab') 2 for considerable hand swelling within one hour of the bite.Edema progressed rapidly to the elbow, severely limiting wrist flexion and extension.Dorsal and volar aspects of the hand revealed significant ecchymoses.The treating physician administered another ten vials of F(ab') 2 two hours later.Swelling briefly continued to spread into the bicep during transfer to a tertiary hospital but stabilized on arrival without additional antivenom.All laboratory values were within normal limits.The patient was monitored for 18 h after the second dose of antivenom without further complications.Eight days post discharge, patient reported that his left hand edema had improved and deferred his followup appointment.

Case 3
A 31-year-old male presented with severe pain and edema extending to the wrist after envenomation of the right index finger by an Agkistrodon contortrix sustained while reaching under a tractor.Swelling spread to the elbow within two hours of envenomation, at which time he received ten vials of F(ab') 2 .Five hours later, patient received an additional ten vials of F(ab') 2 due to increasing edema.The swelling temporarily appeared controlled but progressed into the bicep 14 h after the second dose of F(ab') 2 .Twenty hours after envenomation, he received six vials of Fab, and swelling stabilized; the change in antivenom was at the discretion of the treating physician.The patient remained hospitalized for three days with no hematologic abnormalities or further increases in swelling.Within a week of hospital discharge, the patient moved out of state preventing follow-up.

Case 4
An 11-year-old female was envenomated by an Agkistrodon contortrix on her left index finger while chasing frogs.She received ten vials of F(ab') 2 for hand edema two hours post envenomation.Following F(ab') 2 , she continued to develop rapid swelling of her left upper extremity up to her elbow limiting range of motion of her wrist, elbow, and shoulder.She was subsequently transferred to a pediatric tertiary care facility that stocks only Fab.A bedside medical toxicologist administered four Fab vials six hours post envenomation aborting edema progression.Within 2 weeks of discharge, tissue swelling had resolved; however, at 2 month follow-up, she reported ongoing mild paresthesias in all fingers of her left hand without evidence of muscle wasting or joint dysfunction.

Discussion
The F(ab') 2 clinical trial demonstrated superiority over Fab in preventing late coagulopathy, but clinically significant hemotoxicity is rare with copperheads.In Agkistrodons, the primary concern remains control of tissue damage, an outcome that the trial did not assess [2,7].While almost all venomous snakes in the United States belong to the crotalinae family, there is significant regional variation in individual species [8].Ten of the 18 sites in the F(ab') 2 phase 3 trial were located in Arizona, New Mexico, or California, where rattlesnakes are the predominant venomous snakes [9].As a result, Agkistrodon envenomations accounted for only 22 of the 114 study patients [2].In contrast to the US southwest, Agkistrodons are responsible for the majority of venomous snakebites in many eastern states which may limit the study's geographical applicability [8].
High quality research on the F(ab') 2 is limited and results lack validation.One mouse model studying neutralization of pit viper venom suggested F(ab') 2 offered advantages in treating hemorrhagic toxicity, but Fab was superior in neutralizing venom components as a whole and was more efficacious than F(ab') 2 at neutralizing the Agkistrodon venom components.The authors suggest that this benefit is derived from the inclusion of an Agkistrodon species (A.piscivorous) in the production of Fab while F(ab') 2 is produced exclusively using venom from rattlesnakes not native to the United States.
A post-hoc subgroup analysis of the copperhead envenomations which contributed to F(ab') 2 receiving FDA approval for all North American pit vipers did not detect differences in achieving control [3].However, this study was limited by the sample size and varied F(ab') 2 regimens, some of which included maintenance doses not recommended in the FDA approved dosing [3,4].A subsequent case report of a 77-year-old male envenomated on his nondominant hand by an Agkistrodon laticinctus did report control of swelling following 10 vials of F(ab') 2 , although he later received 4 vials 30 h post envenomation due to declining platelet counts [10].
Our case series is limited by being an observation of only 4 copperhead envenomations (Table 1).The true denominator of Agkistrodon bites that require additional treatment is not well defined.However, in our clinical experience, control of cytotoxic tissue damage and edema progression is usually obtained with initial Fab loading and maintenance Fab dose is almost always deferred.Often the decision to administer more antivenom may be subjective with wide practice variability.None of our four patients experienced any laboratory abnormalities (Table 2), but all developed significant edema that worsened despite initial F(ab') 2 administration.In three cases, symptom control occurred only after a switch to Fab, although it is unclear whether the change in antivenom was responsible for the response.
As F(ab') 2 becomes more widely available, its use is increasing in regions with a predominance of Agkistrodons.Future research should explore the relative effectiveness of Fab and F(ab') 2 antivenoms in Agkistrodon envenomations in the southeastern US.

Conclusion
In this series of patients with copperhead (Agkistrodon contortrix) envenomations, the manufacturerrecommended dose of 10 vials of F(ab') 2 was insufficient to achieve initial control.Two patients received another 10 vials of F(ab') 2 , and three received Fab before achieving initial control.It is possible that Fab may be more effective than F(ab') 2 in treating copperhead envenomations.Higher quality data are desperately needed.