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Low incidence of early reactions to horse-derived F(ab′)2 antivenom for snakebites in Thailand
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Acta Tropica 105 (2008) 203–205
Short communication
Low incidence of early reactions to horse-derived F(ab)2 antivenom for snakebites in Thailand Aegachai Thiansookon, Ponlapat Rojnuckarin ∗ Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand Received 2 July 2007; received in revised form 26 August 2007; accepted 29 September 2007 Available online 5 October 2007
Abstract 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. © 2007 Elsevier B.V. All rights reserved. Keywords: Antivenom; Snakebite; Hypersensitivity reaction; Skin test
1. Introduction Venomous snakebite is still a common public health problem in Southeast Asia (WHO, 2005). Antivenom is the key remedy for the systemic envenomation by promptly reversing coaulopathy, while the efficacy for local tissue damages is less pronounced (Warrell et al., 1986; Sellahewa et al., 1995; Pardal et al., 2004; Rojnuckarin et al., 2006). However, potentially life-threatening hypersensitivity reactions prohibit universal antivenom administration to all snakebite victims. In Thailand, only patients exhibiting systemic symptoms are indicated for antivenom. However, the incidences of antivenom reactions vary greatly ranging from 1.7 to 84% (Cardoso et al., 1993; Moran et al., 1998; Fan et al., 1999; Gawarammana et al., 2004; Bentur et al., 2004). These depend on sources, purity and production methods of antivenoms. In order to prevent reactions, several pre-medications had been studied. Randomized controlled trials showed that an antihistamine, promethazine, alone was not effective (Fan et al., 1999) but either low dose adrenaline
∗
Corresponding author. E-mail address: [email protected] (P. Rojnuckarin).
0001-706X/$ – see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.actatropica.2007.09.007
(Premawardhena et al., 1999) or combined hydrocortisone and chlorpheniramine could reduce the reactions (Gawarammana et al., 2004). Nevertheless, the latter two studies were subjected to criticism for premature termination and the small sample size, respectively. Current antivenoms are derived from animal sources that may provoke allergic reactions mediated by immunoglobulin E (IgE). Furthermore, the IgG in antivenoms may aggregate and stimulate complement components via its Fc portion resulting in anaphylactic reactions. The latter mechanism was shown to be the main cause of antivenom reactions (Malasit et al., 1986). This leads to the World Health Organization (WHO) recommendation against the use of skin test before antivenom administration to detect IgE-mediated hypersensitivity. Not only it cannot predict the reactions, but also may delay this essential treatment (Warrell, 1990; WHO, 2005). Although data indicate that negative skin test is not associated with reactions, information regarding the courses of patients with positive skin tests is insufficient. Albeit uncommon, IgE-mediated reactions may theoretically occur. It remains unclear if there should be special precautions for these cases including appropriate pre-medications or desensitization. Currently, the leaflets of antivenoms used in Thailand still recommend pre-treatment skin test.
204
A. Thiansookon, P. Rojnuckarin / Acta Tropica 105 (2008) 203–205
Table 1 Symptoms and clinical courses of nine patients with early reactions to antivenoms Case
Symptoms
Antivenom
Treatments
Continued antivenom
Recurrent reactions
1 2 3 4 5 6 7 8 9
Hypotension and rash Hypotension and rash Hypotension and rash Chest pain and rash Urticaria Urticaria Maculopapular rash Maculopapular rash Maculopapular rash
Cobra Cobra Green pit viper Green pit viper Green pit viper Cobra Cobra Green pit viper Green pit viper
Adrenaline; dexamethasone Adrenaline; dexamethasone Adrenaline; dexamethasone Dexamethasone; chlorpheniramine Chlorpheniramine Chlorpheniramine Chlorpheniramine Chlorpheniramine Chlorpheniramine
No Yes No No No Yes Yes Yes Yes
Not applicable No Not applicable Not applicable Not applicable No No No No
The data of the incidence of antivenom reactions will be helpful for clinical decision to give antivenom balancing the risk and benefit ratios and the roles of pre-medications will be considered, if the incidence is high. 2. Patients and methods The medical records of patients admitted to King Chulalongkorn Memorial hospital from January 1997 to August 2006 and diagnosed as venomous snakebites were reviewed (ICD10 = T63.0). Only cases over 15 years old and received antivenom were included. Antivenoms were lyophilized equine F(ab )2 species-specific antibody produced from Saovabha Memorial Institute, Bangkok, Thailand. After the whole IgG was trypsin-treated to digest the Fc portion, unwanted proteins were removed by thermocoagulation, ammonium sulfate fractionation and precipitation of non-IgG molecules using caprylic acid according to the WHO recommendations (Theakston et al., 2003). The indications for viper bites were un-clotted blood, low platelet counts or systemic bleeding. For cobra, it was descending paralysis. One antivenom dose for vipers and cobra was 3 and 10 vials, respectively. Trained nursing staff performed immediate hypersensitivity skin test at the ward. Twenty microliters of 1:100 dilution of antivenom or normal saline were injected intradermally. Wheals twice the sizes of saline control with flares at 15 min were regarded as positive. Antivenoms were dissolved in 100 ml of fluid and infused intravenously in 1 h. Vital signs and abnormal symptoms were recorded every 15 min during infusion and, later, every 4–6 h. Every patient continued staying in the ward for at least 6 h after finishing the course of antivenom for repeated clinical and coagulation assessments. Most patients stayed for 24 h or more. The definition of hypotension was blood pressure of 90/60 mmHg or lower. The patients were advised to come back for the symptoms of serum sickness. Desensitization was started from 1 ml of 1:100,000 dilution of antivenoms intravenously. Doses were increased by 2–2.5 folds every 15 min, if there was no reaction, until reaching undiluted antivenom. We stopped performing desensitization in the latter half of the study. 3. Results There were 382 admitted cases of venomous snakebites during the study period. Two hundred and fifty-fours received
antivenoms with the average 1.75 doses per patient, ranging from 1 to 5. Sixty-six percent (168) of them were male. The mean age was 39.3 ± 16.3 years (mean ± SD). The antivenoms were for Green pit vipers, cobras, Russell’s viper and Malayan pit viper in 212 (83.5%), 32 (12.6%), 6 (2.4%) and 4 (1.6%), respectively. Skin test was performed in 211 cases (83%). The test was reported as positive in 10 (4.7%). Five underwent desensitization. Undiluted antivenoms were administered to the other five under close observation. Chlorpheniramine was given in one case. There was no reaction in any of the skin test positive patients. Reactions to antivenom were noted in nine cases (3.5%). All occurred on the first dose of antivenoms. Five received green pit viper and four cobra antivenoms. Notably, cobra antivenom caused more reactions than viper antivenom (odd ratio 6.2, 95% confident interval 1.6–24.5, p = 0.016 by Chi square test). Severe reactions defined as hypotension or chest symptoms were found in 4 (1.6%). All patients responded well to the adrenaline and/or antihistamine and/or steroid (Table 1). In five, antivenoms were re-given at the intended doses without any recurrent reactions. All patients completely recovered. No patients came back for the symptoms of serum sickness. Seven of nine cases with reactions to antivenoms showed negative skin test before administration. Skin test was not performed in the remaining two. Therefore, 0/10 (0%) cases with positive test and 7/194 (3.6%) of negative cases showed adverse reactions to antivenom. 4. Discussion The incidence of antivenom hypersensitivity in this study is low (3.5%) compared with our previous study (20.8%) using the whole IgG molecule (Rojnuckarin et al., 1998). As Fc removal is associated with fewer side effects, this suggests that Fc-mediated anaphylactic reaction is a mechanism of this adverse reaction. However, higher purity of newer antivenom resulting in lower total protein administration and lesser contamination may also contribute to the lower incidence of the reactions. In this study, cobra antivenom caused significantly more early reactions than those of vipers (12.5% vs. 2.3%, respectively). As all patients manifested reactions on the first dose, one possible reason is that higher doses of antivenom were used (10 vials vs. 3 vials) for cobras resulting in more protein load. Alternatively, cobra
A. Thiansookon, P. Rojnuckarin / Acta Tropica 105 (2008) 203–205
venom that contains a complement activator (Kock et al., 2004) may lower the threshold of anaphylaxis to antivenom. From these data, the decision to give antivenom in Thailand should be more liberal because of the lower concern regarding severe reactions. Nevertheless, the cost and limited supplies are still problematic. In addition, our results do not support the routine use of pre-medication for antivenoms from Thailand. All tested cases that suffered from reactions showed negative test results (sensitivity = 0). This underscores the close observation for all patients receiving antivenom regardless of skin test results. Our previous study using partially purified antivenom demonstrated increased reaction rates for skin test positive patients (odd ratio 2.99) (Rojnuckarin et al., 1998). It is possible that contaminating horse proteins might cause IgE-mediated reactions. However, no reactions occurred in test positive patients in this study (positive predictive value = 0). This may be partially explained by the high purity of newer antivenom that showed only 4.7% positive skin test compared with 8.8% from our previous study (Rojnuckarin et al., 1998). There were no reactions in any skin test positive patients regardless of desensitization. Therefore, our results are consistent with WHO recommendation not to perform skin test in patients requiring antivenom. In conclusion, the low incidence of reactions to antivenom and non-predictive role of skin test suggests changes in the clinical practice guideline for snakebites in Thailand. References Bentur, Y., Raikhlin-Eisenkraft, B., Galperin, M., 2004. Evaluation of antivenom therapy in Vipera palaestinae bites. Toxicon 44, 53–57. Cardoso, J.L., Fan, H.W., Franca, F.O., Jorge, M.T., Leite, R.P., Nishioka, S.A., Avila, A., Sano-Martins, I.S., Tomy, S.C., Santoro, M.L., Chudzinski, A.M., Castro, S.C.B., Kamiguti, A.S., Kelen, E.M.A., Hirata, M.H., Mirandola, R.M.S., Theakston, R.G.D., Warrell, D.A., 1993. Randomized comparative trial of three antivenoms in the treatment of envenoming by lance-headed vipers (Bothrops jararaca) in Sao Paulo, Brazil. Q. J. Med. 86, 315–325. Fan, H.W., Marcopito, L.F., Cardoso, J.L., Franca, F.O., Malaque, C.M., Ferrari, R.A., Theakston, R.D., Warrell, D.A., 1999. Sequential randomised and double blind trial of promethazine prophylaxis against early anaphylactic reactions to antivenom for bothrops snakebites. Br. Med. J. 318, 1451–1452. Gawarammana, I.B., Kularatne, S.A., Dissanayake, W.P., Kumarasiri, R.P., Senanayake, N., Ariyasena, H., 2004. Parallel infusion of hydrocorti-
205
sone ± chlorpheniramine bolus injection to prevent acute adverse reactions to antivenom for snakebites. Med. J. Aust. 180, 20–23. Kock, M.A., Hew, B.E., Bammert, H., Fritzinger, D.C., Vogel, C.W., 2004. Structure and function of recombinant cobra venom factor. J. Biol. Chem. 279, 30836–30843. Malasit, P., Warrell, D.A., Chanthavanich, P., Viravan, C., Mongkolsapaya, J., Singhthong, B., Supich, C., 1986. Prediction, prevention, and mechanism of early (anaphylactic) antivenom reactions in victims of snake bites. Br. Med. J. 292, 17–20. Moran, N.F., Newman, W.J., Theakston, R.D., Warrell, D.A., Wilkinson, D., 1998. High incidence of early anaphylactoid reaction to SAIMR polyvalent snake antivenom. Trans. R. Soc. Trop. Med. Hyg. 92, 69–70. Pardal, P.P., Souza, S.M., Monteiro, M.R., Fan, H.W., Cardoso, J.L., Franca, F.O., Tomy, S.C., Sano-Martins, I.S., de Sousa-e-Silva, M.C., Colombini, M., Kodera, N.F., Moura-da-Silva, A.M., Cardoso, D.F., Velarde, D.T., Kamiguti, A.S., Theakston, R.D., Warrell, D.A., 2004. Clinical trial of two antivenoms for the treatment of Bothrops and Lachesis bites in the Northeastern Amazon region of Brazil. Trans. R. Soc. Trop. Med. Hyg. 98, 28–42. Premawardhena, A.P., de Silva, C.E., Fonseka, M.M., Gunatilake, S.B., de Silva, H.J., 1999. Low dose subcutaneous adrenaline to prevent acute adverse reactions to antivenom serum in people bitten by snakes: randomised, placebo controlled trial. Br. Med. J. 318, 1041–1043. Rojnuckarin, P., Chanthawibun, W., Noiphrom, J., Pakmanee, N., Intragumtornchai, T., 2006. A randomized, double blind, placebo-controlled trial of antivenom for local effects of green pit viper bites. Trans. R. Soc. Trop. Med. Hyg. 100, 879–884. Rojnuckarin, P., Mahasandana, S., Intragumthornchai, T., Sutcharitchan, P., Swasdikul, D., 1998. Prognostic factors of green pit viper bites. Am. J. Trop. Med. Hyg. 58, 22–25. Sellahewa, K.H., Gunawardena, G., Kumararatne, M.P., 1995. Efficacy of antivenom in the treatment of severe local envenomation by the hump-nosed viper (Hypnale hypnale). Am. J. Trop. Med. Hyg. 53, 260–262. Theakston, R.D., Warrell, D.A., Griffiths, E., 2003. Report of a WHO workshop on the standardization and control of antivenoms. Toxicon 41, 541–557. Warrell, D.A., Looareesuwan, S., Theakston, R.D., Phillips, R.E., Chanthavanich, P., Viravan, C., Supanaranond, W., Karbwang, J., Ho, M., Hutton, R.A., Vejcho, A., 1986. Randomized comparative trial of three monospecific antivenoms for bites by the Malayan pit viper (Calloselasma rhodostoma) in southern Thailand: clinical and laboratory correlations. Am. J. Trop. Med. Hyg. 35, 1235–1247. Warrell, D.A., 1990. Treatment of snakebite in the Asia-Pacific Region: a personal view. In: Gopalakrishnakone, P., Chou, L.M. (Eds.), Snakes of Medical Importance (Asia Pacific Region). International Society of Toxinology, Singapore, pp. 641–670. World Health Organization, 2005. Guidelines for the Clinical Management of Snake bites in the South-East Asia Region. World Health Organization, Geneva.
Acta Tropica 105 (2008) 203–205
Short communication
Low incidence of early reactions to horse-derived F(ab)2 antivenom for snakebites in Thailand Aegachai Thiansookon, Ponlapat Rojnuckarin ∗ Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand Received 2 July 2007; received in revised form 26 August 2007; accepted 29 September 2007 Available online 5 October 2007
Abstract 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. © 2007 Elsevier B.V. All rights reserved. Keywords: Antivenom; Snakebite; Hypersensitivity reaction; Skin test
1. Introduction Venomous snakebite is still a common public health problem in Southeast Asia (WHO, 2005). Antivenom is the key remedy for the systemic envenomation by promptly reversing coaulopathy, while the efficacy for local tissue damages is less pronounced (Warrell et al., 1986; Sellahewa et al., 1995; Pardal et al., 2004; Rojnuckarin et al., 2006). However, potentially life-threatening hypersensitivity reactions prohibit universal antivenom administration to all snakebite victims. In Thailand, only patients exhibiting systemic symptoms are indicated for antivenom. However, the incidences of antivenom reactions vary greatly ranging from 1.7 to 84% (Cardoso et al., 1993; Moran et al., 1998; Fan et al., 1999; Gawarammana et al., 2004; Bentur et al., 2004). These depend on sources, purity and production methods of antivenoms. In order to prevent reactions, several pre-medications had been studied. Randomized controlled trials showed that an antihistamine, promethazine, alone was not effective (Fan et al., 1999) but either low dose adrenaline
∗
Corresponding author. E-mail address: [email protected] (P. Rojnuckarin).
0001-706X/$ – see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.actatropica.2007.09.007
(Premawardhena et al., 1999) or combined hydrocortisone and chlorpheniramine could reduce the reactions (Gawarammana et al., 2004). Nevertheless, the latter two studies were subjected to criticism for premature termination and the small sample size, respectively. Current antivenoms are derived from animal sources that may provoke allergic reactions mediated by immunoglobulin E (IgE). Furthermore, the IgG in antivenoms may aggregate and stimulate complement components via its Fc portion resulting in anaphylactic reactions. The latter mechanism was shown to be the main cause of antivenom reactions (Malasit et al., 1986). This leads to the World Health Organization (WHO) recommendation against the use of skin test before antivenom administration to detect IgE-mediated hypersensitivity. Not only it cannot predict the reactions, but also may delay this essential treatment (Warrell, 1990; WHO, 2005). Although data indicate that negative skin test is not associated with reactions, information regarding the courses of patients with positive skin tests is insufficient. Albeit uncommon, IgE-mediated reactions may theoretically occur. It remains unclear if there should be special precautions for these cases including appropriate pre-medications or desensitization. Currently, the leaflets of antivenoms used in Thailand still recommend pre-treatment skin test.
204
A. Thiansookon, P. Rojnuckarin / Acta Tropica 105 (2008) 203–205
Table 1 Symptoms and clinical courses of nine patients with early reactions to antivenoms Case
Symptoms
Antivenom
Treatments
Continued antivenom
Recurrent reactions
1 2 3 4 5 6 7 8 9
Hypotension and rash Hypotension and rash Hypotension and rash Chest pain and rash Urticaria Urticaria Maculopapular rash Maculopapular rash Maculopapular rash
Cobra Cobra Green pit viper Green pit viper Green pit viper Cobra Cobra Green pit viper Green pit viper
Adrenaline; dexamethasone Adrenaline; dexamethasone Adrenaline; dexamethasone Dexamethasone; chlorpheniramine Chlorpheniramine Chlorpheniramine Chlorpheniramine Chlorpheniramine Chlorpheniramine
No Yes No No No Yes Yes Yes Yes
Not applicable No Not applicable Not applicable Not applicable No No No No
The data of the incidence of antivenom reactions will be helpful for clinical decision to give antivenom balancing the risk and benefit ratios and the roles of pre-medications will be considered, if the incidence is high. 2. Patients and methods The medical records of patients admitted to King Chulalongkorn Memorial hospital from January 1997 to August 2006 and diagnosed as venomous snakebites were reviewed (ICD10 = T63.0). Only cases over 15 years old and received antivenom were included. Antivenoms were lyophilized equine F(ab )2 species-specific antibody produced from Saovabha Memorial Institute, Bangkok, Thailand. After the whole IgG was trypsin-treated to digest the Fc portion, unwanted proteins were removed by thermocoagulation, ammonium sulfate fractionation and precipitation of non-IgG molecules using caprylic acid according to the WHO recommendations (Theakston et al., 2003). The indications for viper bites were un-clotted blood, low platelet counts or systemic bleeding. For cobra, it was descending paralysis. One antivenom dose for vipers and cobra was 3 and 10 vials, respectively. Trained nursing staff performed immediate hypersensitivity skin test at the ward. Twenty microliters of 1:100 dilution of antivenom or normal saline were injected intradermally. Wheals twice the sizes of saline control with flares at 15 min were regarded as positive. Antivenoms were dissolved in 100 ml of fluid and infused intravenously in 1 h. Vital signs and abnormal symptoms were recorded every 15 min during infusion and, later, every 4–6 h. Every patient continued staying in the ward for at least 6 h after finishing the course of antivenom for repeated clinical and coagulation assessments. Most patients stayed for 24 h or more. The definition of hypotension was blood pressure of 90/60 mmHg or lower. The patients were advised to come back for the symptoms of serum sickness. Desensitization was started from 1 ml of 1:100,000 dilution of antivenoms intravenously. Doses were increased by 2–2.5 folds every 15 min, if there was no reaction, until reaching undiluted antivenom. We stopped performing desensitization in the latter half of the study. 3. Results There were 382 admitted cases of venomous snakebites during the study period. Two hundred and fifty-fours received
antivenoms with the average 1.75 doses per patient, ranging from 1 to 5. Sixty-six percent (168) of them were male. The mean age was 39.3 ± 16.3 years (mean ± SD). The antivenoms were for Green pit vipers, cobras, Russell’s viper and Malayan pit viper in 212 (83.5%), 32 (12.6%), 6 (2.4%) and 4 (1.6%), respectively. Skin test was performed in 211 cases (83%). The test was reported as positive in 10 (4.7%). Five underwent desensitization. Undiluted antivenoms were administered to the other five under close observation. Chlorpheniramine was given in one case. There was no reaction in any of the skin test positive patients. Reactions to antivenom were noted in nine cases (3.5%). All occurred on the first dose of antivenoms. Five received green pit viper and four cobra antivenoms. Notably, cobra antivenom caused more reactions than viper antivenom (odd ratio 6.2, 95% confident interval 1.6–24.5, p = 0.016 by Chi square test). Severe reactions defined as hypotension or chest symptoms were found in 4 (1.6%). All patients responded well to the adrenaline and/or antihistamine and/or steroid (Table 1). In five, antivenoms were re-given at the intended doses without any recurrent reactions. All patients completely recovered. No patients came back for the symptoms of serum sickness. Seven of nine cases with reactions to antivenoms showed negative skin test before administration. Skin test was not performed in the remaining two. Therefore, 0/10 (0%) cases with positive test and 7/194 (3.6%) of negative cases showed adverse reactions to antivenom. 4. Discussion The incidence of antivenom hypersensitivity in this study is low (3.5%) compared with our previous study (20.8%) using the whole IgG molecule (Rojnuckarin et al., 1998). As Fc removal is associated with fewer side effects, this suggests that Fc-mediated anaphylactic reaction is a mechanism of this adverse reaction. However, higher purity of newer antivenom resulting in lower total protein administration and lesser contamination may also contribute to the lower incidence of the reactions. In this study, cobra antivenom caused significantly more early reactions than those of vipers (12.5% vs. 2.3%, respectively). As all patients manifested reactions on the first dose, one possible reason is that higher doses of antivenom were used (10 vials vs. 3 vials) for cobras resulting in more protein load. Alternatively, cobra
A. Thiansookon, P. Rojnuckarin / Acta Tropica 105 (2008) 203–205
venom that contains a complement activator (Kock et al., 2004) may lower the threshold of anaphylaxis to antivenom. From these data, the decision to give antivenom in Thailand should be more liberal because of the lower concern regarding severe reactions. Nevertheless, the cost and limited supplies are still problematic. In addition, our results do not support the routine use of pre-medication for antivenoms from Thailand. All tested cases that suffered from reactions showed negative test results (sensitivity = 0). This underscores the close observation for all patients receiving antivenom regardless of skin test results. Our previous study using partially purified antivenom demonstrated increased reaction rates for skin test positive patients (odd ratio 2.99) (Rojnuckarin et al., 1998). It is possible that contaminating horse proteins might cause IgE-mediated reactions. However, no reactions occurred in test positive patients in this study (positive predictive value = 0). This may be partially explained by the high purity of newer antivenom that showed only 4.7% positive skin test compared with 8.8% from our previous study (Rojnuckarin et al., 1998). There were no reactions in any skin test positive patients regardless of desensitization. Therefore, our results are consistent with WHO recommendation not to perform skin test in patients requiring antivenom. In conclusion, the low incidence of reactions to antivenom and non-predictive role of skin test suggests changes in the clinical practice guideline for snakebites in Thailand. References Bentur, Y., Raikhlin-Eisenkraft, B., Galperin, M., 2004. Evaluation of antivenom therapy in Vipera palaestinae bites. Toxicon 44, 53–57. Cardoso, J.L., Fan, H.W., Franca, F.O., Jorge, M.T., Leite, R.P., Nishioka, S.A., Avila, A., Sano-Martins, I.S., Tomy, S.C., Santoro, M.L., Chudzinski, A.M., Castro, S.C.B., Kamiguti, A.S., Kelen, E.M.A., Hirata, M.H., Mirandola, R.M.S., Theakston, R.G.D., Warrell, D.A., 1993. Randomized comparative trial of three antivenoms in the treatment of envenoming by lance-headed vipers (Bothrops jararaca) in Sao Paulo, Brazil. Q. J. Med. 86, 315–325. Fan, H.W., Marcopito, L.F., Cardoso, J.L., Franca, F.O., Malaque, C.M., Ferrari, R.A., Theakston, R.D., Warrell, D.A., 1999. Sequential randomised and double blind trial of promethazine prophylaxis against early anaphylactic reactions to antivenom for bothrops snakebites. Br. Med. J. 318, 1451–1452. Gawarammana, I.B., Kularatne, S.A., Dissanayake, W.P., Kumarasiri, R.P., Senanayake, N., Ariyasena, H., 2004. Parallel infusion of hydrocorti-
205
sone ± chlorpheniramine bolus injection to prevent acute adverse reactions to antivenom for snakebites. Med. J. Aust. 180, 20–23. Kock, M.A., Hew, B.E., Bammert, H., Fritzinger, D.C., Vogel, C.W., 2004. Structure and function of recombinant cobra venom factor. J. Biol. Chem. 279, 30836–30843. Malasit, P., Warrell, D.A., Chanthavanich, P., Viravan, C., Mongkolsapaya, J., Singhthong, B., Supich, C., 1986. Prediction, prevention, and mechanism of early (anaphylactic) antivenom reactions in victims of snake bites. Br. Med. J. 292, 17–20. Moran, N.F., Newman, W.J., Theakston, R.D., Warrell, D.A., Wilkinson, D., 1998. High incidence of early anaphylactoid reaction to SAIMR polyvalent snake antivenom. Trans. R. Soc. Trop. Med. Hyg. 92, 69–70. Pardal, P.P., Souza, S.M., Monteiro, M.R., Fan, H.W., Cardoso, J.L., Franca, F.O., Tomy, S.C., Sano-Martins, I.S., de Sousa-e-Silva, M.C., Colombini, M., Kodera, N.F., Moura-da-Silva, A.M., Cardoso, D.F., Velarde, D.T., Kamiguti, A.S., Theakston, R.D., Warrell, D.A., 2004. Clinical trial of two antivenoms for the treatment of Bothrops and Lachesis bites in the Northeastern Amazon region of Brazil. Trans. R. Soc. Trop. Med. Hyg. 98, 28–42. Premawardhena, A.P., de Silva, C.E., Fonseka, M.M., Gunatilake, S.B., de Silva, H.J., 1999. Low dose subcutaneous adrenaline to prevent acute adverse reactions to antivenom serum in people bitten by snakes: randomised, placebo controlled trial. Br. Med. J. 318, 1041–1043. Rojnuckarin, P., Chanthawibun, W., Noiphrom, J., Pakmanee, N., Intragumtornchai, T., 2006. A randomized, double blind, placebo-controlled trial of antivenom for local effects of green pit viper bites. Trans. R. Soc. Trop. Med. Hyg. 100, 879–884. Rojnuckarin, P., Mahasandana, S., Intragumthornchai, T., Sutcharitchan, P., Swasdikul, D., 1998. Prognostic factors of green pit viper bites. Am. J. Trop. Med. Hyg. 58, 22–25. Sellahewa, K.H., Gunawardena, G., Kumararatne, M.P., 1995. Efficacy of antivenom in the treatment of severe local envenomation by the hump-nosed viper (Hypnale hypnale). Am. J. Trop. Med. Hyg. 53, 260–262. Theakston, R.D., Warrell, D.A., Griffiths, E., 2003. Report of a WHO workshop on the standardization and control of antivenoms. Toxicon 41, 541–557. Warrell, D.A., Looareesuwan, S., Theakston, R.D., Phillips, R.E., Chanthavanich, P., Viravan, C., Supanaranond, W., Karbwang, J., Ho, M., Hutton, R.A., Vejcho, A., 1986. Randomized comparative trial of three monospecific antivenoms for bites by the Malayan pit viper (Calloselasma rhodostoma) in southern Thailand: clinical and laboratory correlations. Am. J. Trop. Med. Hyg. 35, 1235–1247. Warrell, D.A., 1990. Treatment of snakebite in the Asia-Pacific Region: a personal view. In: Gopalakrishnakone, P., Chou, L.M. (Eds.), Snakes of Medical Importance (Asia Pacific Region). International Society of Toxinology, Singapore, pp. 641–670. World Health Organization, 2005. Guidelines for the Clinical Management of Snake bites in the South-East Asia Region. World Health Organization, Geneva.