Immediate hypersensitivity reaction associated with the rapid infusion of Crotalidae polyvalent immune Fab (ovine)

A 16-year-old boy presented to the emergency department with rapidly progressing extremity pain, edema, and ecchymosis after envenomation by a copperhead. Crotalidae polyvalent immune Fab (ovine) (CroFab; FabAV) was infused. Six vials were placed in 250 mL of normal saline solution, and the infusion was gradually increased. Fifty minutes after beginning, the infusion was increased to 640 mL/h. Within minutes of the rate increase, the patient experienced full-body urticaria, facial edema, voice change, and tachycardia. The infusion was stopped. Hydroxyzine pamoate, famotidine, methylprednisolone, and a 1-L bolus of normal saline solution were administered intravenously. The symptoms abated, and the remaining FabAV was infused at a slower rate without return of this reaction. This immediate hypersensitivity reaction was most likely a rate-related anaphylactoid reaction that has not been previously reported with FabAV.[Holstege CP, Wu J, Baer AB. Immediate hypersensitivity reaction associated with the rapid infusion of Crotalidae polyvalent immune Fab (ovine). Ann Emerg Med. June 2002;39:677-679.]     

Crotalidae polyvalent immune Fab (ovine) antivenom is efficacious for envenomations by Southern Pacific rattlesnakes (Crotalus helleri)

STUDY OBJECTIVE: Southern Pacific rattlesnake (Crotalus helleri ) venom is not 1 of the 4 venoms used to produce Crotalidae polyvalent immune Fab (ovine) (CroFab; FabAV). There is currently no published clinical experience regarding the efficacy of this new antivenom for confirmed C helleri envenomation, and animal data suggest greatly diminished efficacy. We assessed the efficacy of FabAV for patients with confirmed C helleri envenomation. METHODS: We conducted a prospective observational study of 23 consecutive rattlesnake envenomations that were treated with FabAV at our center. Patients were excluded if the species of snake could not be confirmed, if FabAV antivenom was not given, or if Antivenin (Crotalidae) polyvalent (equine) was given. We collected serial physical examination and laboratory data over a 24-hour period to serially evaluate the severity score and performed follow-up to evaluate delayed reactions. RESULTS: There were 15 patients who received FabAV and had the species of rattlesnake confirmed (9 C helleri, 4 C scutulatus scutulatus, 1 C mitchellii pyrrhus, 1 C ruber ruber ). C helleri envenomations demonstrated similar improvement in serial snakebite severity scores to those of other species. Three patients treated with scheduled dosing had recurrence of progressive swelling (2 C helleri and 1 C mitchellii pyrrhus ) during the 24-hour study period. CONCLUSION: We observed similar improvement in FabAV-treated patients with C helleri envenomation compared with those of other species and conclude that this treatment in standard doses appears efficacious for bites by this species. Progressive swelling may recur despite scheduled dosing.     

Crotalidae polyvalent immune Fab antivenom limits the decrease in perfusion pressure of the anterior leg compartment in a porcine crotaline envenomation model

STUDY OBJECTIVE: Crotalidae Polyvalent Immune Fab (CroFab; FabAV) antivenom prevents a decrease in perfusion pressures in intramuscular crotaline envenomation compared with normal saline solution. METHODS: We used a randomized, blinded, controlled acute animal preparation. Twenty anesthetized and instrumented swine were injected intramuscularly with 6 mg/kg Crotalus atrox venom into the anterior tibialis muscle of each hind limb (time 0). One hour after envenomation (time 1 hour), animals were randomized to receive 8 vials of reconstituted FabAV or an equal volume of normal saline solution (control) through a central venous line. The main outcome variable was the area under the perfusion-time curve (AUC) of the anterior compartment of the hind limb measured from time 1 hour to time 8 hours. Perfusion pressure was defined as mean arterial pressure-compartment pressure. Additionally, physiologic variables, including pulse rate, prothrombin time, fibrinogen level, platelet count, hemoglobin level, and hematocrit level, were monitored. RESULTS: Venom injection resulted in a decrease in average perfusion pressures from 54.1 mm Hg (time 0) to 31.7 mm Hg (time 1 hour). Comparison of AUC between groups from time 1 hour (time of treatment) to the completion of the study at time 8 hours revealed a 57% greater AUC in animals that received FabAV (mean+/-SD: 211.1+/-67.9 versus 134.5+/-55.8 mm Hg/h; P =.036; 95% confidence interval for difference 5.9 to 147.3). Comparison of the time curves for the mean prothrombin time from time 1 hour to the completion of the study by means of repeated-measures analysis of variance revealed a significant increase in the control group (P =.02). No significant difference was detected in the time curves for the means of mean arterial pressure, compartment pressure, pulse rate, hemoglobin level, hematocrit level, fibrinogen level, or platelet count over the course of the study. FabAV was found to significantly increase survival time when compared with the effect of the normal saline solution control from time 1 hour to time 8 hours, as determined by means of Kaplan-Meier estimation and the log-rank test (P =.029). CONCLUSION: FabAV limits the decrease in perfusion pressures in the anterior leg compartment after intramuscular crotaline venom injection in swine compared with saline solution. In addition, FabAV might prevent the development of coagulopathy and increase survival time in this model.     

A randomized multicenter trial of crotalinae polyvalent immune Fab (ovine) antivenom for the treatment for crotaline snakebite in the United States

BACKGROUND: Current therapy for crotaline snakebite includes antivenin (Crotalidae) polyvalent, an antivenom with numerous adverse effects. We compared the efficacy and safety of 2 dosing regimens with a new antivenom, Crotalinae polyvalent immune Fab (Fab AV). METHODS: A single dose of Fab AV alone (as-needed [PRN] group) was compared with an initial dose plus repeated treatments during 18 hours (scheduled group) in a multicenter randomized trial. The study included patients with minimal or moderate envenomation by a crotaline snake within the preceding 6 hours, aged 10 years or older, in whom worsening of the envenomation syndrome was observed before Fab AV treatment. After treatment with Fab AV to achieve initial control, patients were randomized to the scheduled or PRN treatment group. Scheduled group patients received additional doses of Fab AV every 6 hours for 3 doses. The PRN group received no planned additional doses of antivenom. RESULTS: The mean severity score of the 31 patients decreased from 4.35 to 2.39 points (P<.001); there was no difference between scheduled and PRN groups. No patient in the scheduled group received unplanned Fab AV doses, but 8 of 16 patients in the PRN group received unplanned doses (P =.002). Acute reactions occurred in 6 patients (19%), and serum sickness occurred in 6 (23%) of 26 patients who returned for follow-up. CONCLUSIONS: In the first randomized trial of antivenom in the United States, Fab AV effectively terminated venom effects. Since the unplanned use of Fab AV in the PRN group was common, the treatment regimen may require more than 1 initial dose.     

Efficacy of Crotalidae polyvalent antivenin for the treatment of hognosed viper (Porthidium nasutum) envenomation

Envenomation from pit vipers native to North America can be treated successfully with either of the 2 commercially available antivenoms licensed in the United States. However, envenomations from imported snakes held in zoos or private collections often pose unique challenges to management because of the lack of specific antivenom and the unclear efficacy of the available licensed products. We report the case of a 37-year-old man who was envenomated on his left hand by his pet hognosed viper (Porthidium nasutum ). He had swelling at the wound site that progressively worsened over 3 to 4 hours. His symptom progression included the structural motor impairment of his fingers and a sensory deficit. Treatment with 8 vials of Antivenin (Crotalidae) polyvalent was associated with a halt of extremity swelling and restoration of neurologic and motor function of his hand. Limited experimental evidence provides support for antigenic cross-reactivity between Antivenin (Crotalidae) polyvalent and P nasutum venom.     

Cost-effectiveness analysis of the use of digoxin immune Fab(ovine) for treatment of digoxin toxicity

Each year many people have digitalis toxicity severe enough to require extensive hospital treatment. Digoxin immune Fab[ovine]-Fab fragments (Digibind®) have been shown to reverse digitalis toxicity and substantially reduce the risk of death. Data were used from uncontrolled studies of patients treated with Fab fragments as well as clinical, medical care and pharmacokinetic data from symptomatically treated patients to derive estimates of the difference in clinical outcomes and medical care costs when treating with this new drug. Estimates are derived separately for treatment of patients with toxicity that is immediately life-threatening and patients whose manifestations are not immediately life-threatening. Treatment with Fab fragments reduces the probability of dying more for the seriously toxic than for the less seriously toxic patient. Such treatment is generally associated with an increase in total medical care costs for the seriously toxic patients because more of them survive the toxic episode and require additional medical care before discharge from the hospital. For these patients, the estimated cost per life-year saved is between $1,900 and $5,400. When Fab fragments are used to treat less seriously toxic patients, total medical care costs decrease because of an estimated decreased number of days in the coronary care unit and decreased use of pacemakers and other aggressive treatments.     

Incidence of immediate and delayed hypersensitivity to Centruroides antivenom.

STUDY OBJECTIVE: To assess the incidence and course of immediate and delayed hypersensitivity to Centruroides antivenom. METHODS: We performed a 12-month prospective observation study, with telephone follow-up, evaluating the incidence of anaphylaxis or anaphylactoid reactions and serum sickness after Centruroides antivenom administration. The setting for the study was a poison control center and tertiary care toxicology treatment center. Participants included all patients who received Centruroides antivenom, and no interventions were performed. RESULTS: For immediate hypersensitivity reactions, 116 patients with grade III or IV envenomation received Centruroides antivenom; 77 of these patients were younger than 13 years. Three patients completed the infusion despite development of rash. A fourth patient with a history of atopy and asthma received epinephrine infusion and an inhaled beta-agonist for transient wheezing that quickly resolved; she was admitted for observation. Nine patients without hypersensitivity reactions were admitted for social reasons, for inappropriate sedation from drugs used before antivenom, or to rule out aspiration; all were discharged within 24 hours. The remaining 106 patients were discharged from the emergency department after resolution of symptoms. Thus 4 of 116 patients had immediate reactions. For patients with delayed reactions, 17 patients were lost to follow-up. Of 99 remaining patients, serum sickness developed in 61% (n=60), as defined by using liberal criteria. Serum sickness responded to oral steroids, antihistamines, or both; mean duration of symptoms with medication was 2.8 days. CONCLUSION: Anaphylactic reactions are uncommon after Centruroides antivenom infusion. Self-limited serum sickness that is easily controlled with corticosteroids and antihistamines commonly follows the use of Centruroides antivenom.     

Clinical trial of an F(ab')2 polyvalent equine antivenom for African snake bites in Benin

We report the results of a trial designed to measure the safety and efficacy of African Antivipmyn, a new freeze-dried polyvalent equine F(ab')(2)-based antivenom. We tested 289 envenomations. After treatment, 19% of treated patients had undesirable events, all benign. A possible adverse effect was attributed to this antivenom in 11% of the patients. Bleeding was observed in 48% of the patients; it stopped within 2 hours after treatment with antivenom in 60% of the patients. Blood incoagulability was observed in 80% of the patients. Restoration of coagulation was attained within 4 hours in 60% of the patients. Nine patients died; 6 arrived at the hospital in the final stage of complications and 5 arrived at the hospital more than 60 hours after the bite. The value of blood coagulation tests in diagnosis of envenomation and bleeding as an indicator of renewal of treatment are emphasized.     

Immediate hypersensitivity and delayed hypersensitivity to clopidogrel

Clopidogrel is a new antiplatelet prescribed for the secondary prevention of atherosclerotic events. The literature shows that the clinical manifestations of clopidogrel hypersensitivity include urticaria1, skin rash2-4, and angioedema5. The precise immunological mechanism underlying clopidogrel hypersensitivity has not been established. We describe two cases of hypersensitivity reaction due to clopidogrel. The first constituted an immediate reaction after clopidogrel intake. In this case we demonstrated type 1 hypersensitivity using cutaneous tests. The second case represented a delayed hypersensitivity reaction confirmed by oral challenge testing, in which good tolerance to other antiplatelet drugs such as ticlopidine was demonstrated.     

A new monospecific ovine Fab fragment antivenom for treatment of envenoming by the Sri Lankan Russell's viper (Daboia Russelii Russelii): a preliminary dose-finding and pharmacokinetic study.

Russell's viper is the most important cause of life-threatening snake bite and acute renal failure in Sri Lanka. Only equine polyspecific antivenoms imported from India are available. They have not proved effective clinically or in clearing venom antigenemia and they frequently cause reactions. In an attempt to reduce mortality and morbidity, a new monospecific ovine Fab fragment antivenom (PolongaTab; Therapeutic Antibodies, Inc., London, United Kingdom) was raised against Sri Lankan Russell's viper venom. In a preliminary dose-finding study in 35 patients, an initial dose of 3-4 g restored blood coagulability permanently and stopped systemic bleeding, even in severely envenomed patients. Venom antigenemia disappeared within 1 hr of antivenom treatment but recurred, probably as a result of continued absorption of venom from the site of the bite, after the rapid clearance of therapeutic antibody. Twelve patients (34%) experienced early reactions that were usually mild and always responded to epinephrine.     

Cross neutralization of common Southeast Asian viperid venoms by a Thai polyvalent snake antivenom (Hemato Polyvalent Snake Antivenom)

Snake envenomation is a serious public health threat in many rural areas of Asia and Africa. Antivenom has hitherto been the definite treatment for snake envenomation. Owing to a lack of local production of specific antivenom, most countries in these regions fully depend on foreign supplies of antivenoms. Often, the effectiveness of the imported antivenoms against local medically important species has not been validated. This study aimed to assess cross-neutralizing capacity of a recently developed polyvalent antivenom, Hemato Polyvalent Snake Antivenom (HPAV), against venoms of a common viper and some pit vipers from Southeast Asia. Neutralisation assays showed that HPAV was able to effectively neutralize lethality of the common Southeast Asian viperid venoms examined (Calloselasma, Crytelytrops, Popeia, and Daboia sp.) except for Tropidolaemus wagleri venom. HPAV also effectively neutralized the procoagulant and hemorrhagic activities of all the venoms examined, corroboratively supporting the capability of HPAV in neutralizing viperid venoms which are principally hematoxic. The study also indicated that HPAV fully prevented the occurrence of hematuria and proteinuria in mice envenomed with Thai Daboia siamensis venom but was only partially effective against venoms of Myanmar D. siamensis. Thus, HPAV appears to be useful against its homologous venoms and venoms from Southeast Asian viperids including several medically important pit vipers belonging to the Trimeresurus complex. Nevertheless, the effectiveness of HPAV as a paraspecific antivenom for treatment of viperid envenomation in Southeast Asian region requires further assessment from future clinical trials     

Low incidence of early reactions to horse-derived F(ab')(2) antivenom for snakebites in Thailand

Although antivenom is effective for systemic effects of snake envenomation, the possibility of fatal hypersensitivity reactions must be considered. The risks vary greatly among different products and cannot be excluded by negative skin test. However, clinical outcomes of patients with positive skin test remain to be determined. The medical records of 254 cases receiving antivenoms during 1997-2006 were reviewed. Most were for green pit vipers (84%) and cobras (13%). Early reactions occurred in 9 (3.5%) including 3 (1.2%) with hypotension. The incidence was more common after cobra than viper antivenoms (12.5% vs. 2.3%, respectively, p=0.016). Skin test was negative in 7/7 tested cases. All reactions resolved. Antivenoms were re-administered in five without recurrent reactions. Overall, skin test was positive in 10/211 (4.7%). Five of them underwent desensitization. Antivenom can be given in all 10 without reactions. In conclusion, the incidence of early reactions to antivenoms was low in Thailand and skin test is not helpful at all in predicting this adverse reaction.     

Successful re-treatment with cis-dichlorodiammineplatinum(II) after apparent allergic reactions.

Allergic or anaphylactic-like reactions have been reported with cis-dichlorodiammineplatinum(II) (CDDP) administration. We have seen two reactions among 50 patients treated in a phase II trial of CDDP. Both patients were successfully rechallenged after diphenhydramine pretreatment, and therapy was continued. In vivo and in vitro studies performed in one patient included negative skin tests, negative histamine release assay, negative lymphocyte stimulation studies, and normal total serum IgE. We conclude that some apparent allergic reactions occurring with CDDP may have a non-allergic etiology, and treatment may be successfully continued in selected patients.