SNAKEBITE ENVENOMATION and DEATH in the DEVELOPING WORLD Luzia S. Cruz, MD

Home , Bothrops asper, Bothrops atrox, Envenomation

SNAKEBITE ENVENOMATION AND DEATH IN THE DEVELOPING WORLD

The purpose of this review is to address the Luzia S. Cruz, MD; Roberto Vargas, MD, MPH; global incidence and management of snake- Antoˆnio Alberto Lopes, MD, MPH, PhD bite envenomation and to describe the clinical characteristics and pathogenesis of envenomation by species of the family Viperidae, genera Bothrops and Crotalus, the most INTRODUCTION bite envenomation are reported each common venomous snakes in Brazil. We focus year, with an estimated 35,000–50,000 15,24 on the pathogenesis of the acute renal failure Envenoming from poisonous ani- deaths. In Pakistan, there are 24 induced by these snakes. Envenomation after mals, particularly terrestrial venomous <20,000 snakebite deaths annually. snakebite is an underestimated and neglected In Nepal, there are an estimated 20,000 public health issue responsible for substantial snakes, causes substantial illness and illness and death as well as socioeconomic death and represents an economic snakebites and <200 deaths in hospitals hardship to impoverished populations living in hardship on poor, rural populations annually, predominantly in the eastern 4,24 rural and tropical Africa, Asia, Oceania, and and healthcare systems of tropical and Terai. In Vietnam, from 1992 to Latin America. In developed nations, snake subtropical Africa, Asia, Oceania, and 1998, there were an estimated 300,000 bite typically occurs during recreational activ- 1–25 ities, whereas in developing countries it is an Latin America. Although mortality bites per year, and a case fatality ratio of occupational disease more likely to affect from snakebite is estimated to be one- 22% was reported among plantation young agricultural workers, predominantly tenth that of malaria, no equivalent workers bitten by Malayan pit vipers.24 men. Scarcity and delay of administration of global snakebite control program exists. In Mynamar, there were 14,000 bites antivenom, poor health services, and difficul- 24 An international effort is necessary to and 1,000 deaths in 1991. Papua New ties with transportation from rural areas to health centers are major factors that contribute focus global attention on this neglected Guinea has one of the world’s highest 17 17 to the high case-fatality ratio of snakebite and treatable condition. incidence rates of snake bites. In envenomation. (Ethn Dis. 2009;19[Suppl The World Health Organization Africa, the annual incidence rate of 1]:S1-42–S1-46) (WHO) estimates that <2,500,000 snake bites in the Benue Valley of northeastern Nigeria is 497 per Key Words: Snakebite Envenomation, Epi- venomous snakebites per year result in demiology, Pathogenesis, Acute Renal Failure, 125,000 deaths worldwide, 100,000 of 100,000 population, with a case-fatality 4 Clinical Characteristics, Bothrops, Crotalus, which are in Asia and approximately ratio of 12.2%. In northern Africa, the Treatment 20,000 in Africa.5,6 The true global species that causes most bites and deaths incidence of envenomation and its belongs to the family Viperidae, Echis sp severity remain largely misunderstood. (saw-scaled vipers), whereas in Asia Hospital-based data are likely to under- most frequent envenomations result estimate the incidence, the case-fatality from bites by species of the Elapidae ratio, and the overall contribution family, represented by the Naja sp snakebites make to worldwide morbid- (cobras) and Bungarus sp (kraits). In ity and mortality because most victims Central and South America, bites by seek traditional treatment; these victims Bothrops asper and Bothrops atrox (lance- may die at home and their deaths headed pit vipers) predominate.4 In remain unrecorded.4,21 Brazil, the most severe cases of snakebite The objectives of this review are to result from envenomation inflicted by describe the worldwide incidence and species of the family Viperidae, genera treatment of snakebite envenomation, as Bothrops and Crotalus (South American well as clinical characteristics and the rattlesnake). From 1990 to 1993, the From the CLINIRIM, Clıńica do Rim e pathogenesis of common venomous Brazilian Ministry of Health reported Hipertensaõ Arterial Ltda (LSC), Medicine snakebites in Brazil. 65,911 snakebites.1 Bites by snakes of Department, Nephrology Service and Epi- genus Bothrops were responsible for demiology Unit, Federal University of Bahia 90.5%, and bites by Crotalus rattle- (AAL), Salvador, Bahia, Brazil; Department of Medicine, Geffen School of Medicine, EPIDEMIOLOGY snakes accounted for 7.7% of these. 26 University of California at Los Angeles and Bucaretchi et al analyzed hospital RAND Institute, Los Angeles, California (RV). Approximately 3000 species of records of 73 children aged ,15 years snakes exist worldwide, and 410 are who were bitten by Bothrops sp snakes in Address correspondence and reprint 18 Saõ Paulo, Brazil, from January 1984 requests to: Luzia S. Cruz, MD; 1845 considered venomous. The reported Mallard Dr; Panama City, FL 32404; 850- rate of bites from these snakes is high. In through March 1999. Most bites oc- 871-2684; [email protected] India alone, .200,000 cases of snake- curred from October to March, which

S1-42 Ethnicity & Disease, Volume 19, Spring 2009 SNAKE BITE ENVENOMATION - Cruz et al reflects the influence of seasonal factors, consequence, consumption coagulopa- nephrotoxic, leading to acute tubular such as an increase in temperature and thy and partial or complete blood necrosis, the primary and most serious humidity associated with the rainy incoagulability may develop. Envenom- complication of human crotalid enven- season, and also in human agricultural ing by Bothrops sp inflicts severe tissue omation.5,10,13,37–39 Tissue damage at activities, such as planting and harvest- damage, such as swelling, blistering, the site of the bite has been reported to ing. Bothrops jararaca, the most com- hemorrhage, and necrosis of skeletal be minimal or absent, a feature that mon species of Bothrops in southeast muscle. Systemic effects include spon- differentiates the South American rat- Brazil, which was responsible for most taneous hemorrhage (of which cerebral tlesnake from other species of Crotalus. snake bites in this study, is more active hemorrhage is the most serious mani- Spontaneous bleeding has only been during this season and in the evening. festation), disseminated intravascular rarely observed in human patients.1,10,18 The rise in river levels due to tropical coagulation, and cardiovascular shock A prospective survey of 100 cases of rains may cause an inland migration of secondary to hypovolemia and vasodi- C. durissus bites followed from hospi- these snakes.3 lation,1–3,7,16,26,29,34 Bothrops jararaca talization to death or discharge in Sa˜o In developed countries, venomous venom is a potent inhibitor of angio- Paulo, Brazil, revealed a high prevalence snakebites frequently occur during rec- tensin-converting enzyme (ACE) and of acute renal failure (ARF) (29%), reational activities, whereas in the potentiates the hypotensive effect of defined as a creatinine clearance developing world, snakebite is an occu- circulating bradykinin. Murayama et al ,60 mL/min/1.73 m2 in the first pational disease more likely to affect cloned and sequenced cDNA isolated 72 hours after the bite.5 Most cases of young agricultural workers, predomi- from the Bothrops jararaca venom ARF were nonoliguric, and the frac- nantly men.3,8,18,20 The high case- gland; it encodes 2 distinct classes of tional excretion of sodium was signifi- fatality ratio of snakebites in tropical bioactive peptides, bradykinin-potenti- cantly higher in ARF patients. Age developing countries is the result of a ating oligopeptides and a C-type natri- ,12 years was an independent risk combination of factors, including the uretic peptide, which display synergistic factor for ARF, which may be related scarcity of antivenom, poor health effects on blood pressure and most to an increased concentration of the services, and problems with transporta- likely contribute to the cardiovascular venom and a more severe clinical tion from rural areas to health cen- effects caused by Bothrops jararaca picture as a result of a lower blood ters.4,17,19–23,27,28 envenomation.35,36 volume and smaller body surface in children. The case fatality ratio was Crotalus (South 10%. The most important finding in CLINICAL American Rattlesnake) the study was that delay in administer- CHARACTERISTICS Among the species of Crotalus, ing an adequate dose of the crotalid AND PATHOGENESIS Crotalus durissus terrificus is the most antivenom increased the risk of ARF by frequently implicated in envenomation more than 10 times. Therefore, Burd- This section primarily focuses on the in Brazil. The venom of C d terrificus mann et al suggest that antivenom major clinical characteristics and the contains a variety of toxic peptides, should be available in health centers pathogenesis of envenomation by select- including crotoxin, crotamine, giroxin, and emergency services of small com- ed species of snakes that are highly convulxin, and a thrombin-like enzyme. munities rather than concentrated in prevalent in Brazil. Crotoxin is responsible for the high urban reference hospitals. toxicity of the venom and has neuro- Bothrops sp (Lance-headed toxic, myotoxic, and nephrotoxic activ- Pit Vipers) ity. It is a powerful presynaptic neuro- PATHOGENESIS OF Bothrops venom contains various toxin that targets neuromuscular SNAKEBITE-INDUCED ARF biologically active peptides, such as junctions and inhibits the release of metalloprotease, phospholipase, and hy- acetylcholine, which leads to neuromus- Because it is well vascularized, the aluronidases, which may elicit an in- cular blockade and progressive flaccid kidney is a particularly vulnerable organ flammatory response and contribute to paralysis of variable degrees.1,5,10–14 to venom toxicity.6 ARF is a serious cell and tissue injury as well as hemo- Crotoxin also produces severe skeletal complication of venomous snakebites static disturbances.29–33 Most Bothrops muscle injury leading to rhabdomyolysis by the Viperidae family.1,5,10,24,25,40 venom activates coagulation factor X with the subsequent release of myoglo- Snakebite-induced ARF is usually and prothrombin and lyses fibrinogen, bin from damaged skeletal muscle into caused by acute tubular necrosis, but which leads to hypofibrinogenemia and serum and urine. High serum and urine all renal structures may be involved. complete fibrinogen consumption. As a levels of myoglobin are potentially Renal cortical necrosis, acute tubuloin-

Ethnicity & Disease, Volume 19, Spring 2009 S1-43 SNAKE BITE ENVENOMATION - Cruz et al terstitial nephritis, extracapillary prolif- ene B4, thromboxane A2, TNF-a,and includes a number of additional inter- erative glomerulonephritis, mesangioly- IL-6. The study also points out to the ventions, such as maintenance of fluid, sis, and vasculitis have all been de- potential ability of Bothrops jararaca electrolyte balance, and good urine scribed.6,9,34,40–43 Amyriadof venom to activate the endothelium, flow; administration of tetanus toxoid; nephrotoxic insults have been implicat- since adhesion molecules are expressed assisted ventilation; dialysis; use of ed in the pathogenesis of ARF, such as by endothelial cells. acetylcholinesterase inhibitors, preceded nephrotoxicity of venom, hypotension, Snake venom metalloproteinases, by atropine sulfate, in neurotoxic en- circulatory collapse, precipitation of abundant enzymes in crotaline and venomations; early alkalinization of endogenous pigments such as myoglo- viperine snake venoms, administered to urine by sodium bicarbonate in patients bin and hemoglobin in renal tubules, experimental animals trigger a cascade with myoglobinuria or hemoglobinuria; disseminated intravascular coagulation, of inflammatory events, such as release antibiotics in case of development of sepsis, hemodynamic alterations, and of interleukin-1 (IL-1) and IL-6, acti- local infection; and surgical de´bride- cell injury induced by the release of vation of the classic and alternative ment of necrotic tissue. Atropine sulfate proinflammatory cytokines and vasoac- complement system pathways, and in- counteracts the muscarinic effects of tive mediators.6,9 creased expression of mRNA encoding acetylcholine, such as increased respira- Experimental models have been for TNF-a, IL-1, and IL-6 by elicited tory secretions, sweating, bradycardia, attempted to clarify the renal involve- macrophages.30,31,33 and colic. ment in snakebites. In the perfused rat In the perfused rat isolated kidney The use of tourniquets should be isolated kidney model, Castro et al44 model, Martins et al46 demonstrated discouraged. In envenomations from showed that Bothrops jararaca venom that inhibition of synthesis of cytotoxic Bothrops sp, the venom of which directly injures proximal tubules, evi- mediators, possibly TNF-a, by thalido- possesses cytolytic and necrotizing ac- denced by a decrease in glomerular mide and pentoxyfilline reversed all tivity, tourniquets increase the retention filtration rate and renal plasma flow renal alterations induced by superna- of the venom at the bite site and may and an increase in renal vascular tants of macrophages activated with C enhance the extent of local inju- resistance and fractional excretion of durissus cascavella venom. Martins et al ry.1,7,24,49 Pressure immobilization is sodium. were also able to demonstrate that the recommended for bites by neurotoxic Further experimental studies45 have cyclooxygenase inhibitor indomethacin elapid snakes but should not be used for shown that the intraperitoneal injection reversed almost all renal alterations viper bites.24 Fasciotomy is only indi- of Bothrops jararaca venom in rats induced by supernatants of macrophag- cated to treat intracompartmental syn- induced recruitment of polymorphonu- es stimulated by C d cascavella venom. drome after the hemostatic abnormali- clear leukocytes (PMN) into the perito- The fact that the supernatant of macro- ties are properly corrected.1,4–6,9,18,24,25 neal cavity and that pretreatment with phages is free of venom, as shown by New approaches have been devel- anti-mouse intercellular adhesion mole- high performance liquid chromatogra- oped to improve the quality of anti- cule-1 (ICAM-1), platelet endothelial phy analysis, strongly suggests that the venom, such as using DNA immuniza- cell adhesion molecule-1 (PECAM-1), venom itself is not acting directly but tion or the purified relevant toxins as and leukocyte endothelial cell adhesion rather that the macrophages are releas- antigens instead of the whole venom; molecule-1 (LECAM-1) significantly ing mediators, which can promote searching for other animal species from reduced the number of recovered nephrotoxicity. which it is possible to obtain antivenom, PMN. Bothrops jararaca venom induced such as camels and hens; preparing a marked increase in peritoneal leuko- antivenom that combines antibodies triene B4, thromboxane A2, interleu- TREATMENT with recombinant ‘‘nanobodies,’’ which, kin-6 (IL-6), and tumor necrosis factor- by having a very low molecular mass, alpha (TNF-a). These results suggest Antivenom is the only specific may reach tissue compartments more that the PMN influx induced by antidote to snake venom and its timely rapidly than conventional immunoglob- intraperitoneal injection of Bothrops administration completely reverses all ulin G fragments.4,27 jararaca venom in mice is related to systemic manifestations of envenom- Although antivenom is extremely the expression of ICAM-1, PECAM-1, ing.1,4–6,23,25,47 Adverse reactions are efficient in the neutralization of system- and LECAM-1 adhesion molecules, frequent (as high as 87%), may include ic abnormalities, the amelioration of which are responsible for the rolling, anaphylactic shock, and cannot be venom-induced local effects is difficult firm adhesion, and transmigration of predicted by sensitivity tests.47,48 because of the rapid development of PMN and that these effects may be Besides antivenom administration, tissue injury after envenomation and the indirect through the release of leukotri- the treatment of snakebite envenoming delay in reaching health centers where

S1-44 Ethnicity & Disease, Volume 19, Spring 2009 SNAKE BITE ENVENOMATION - Cruz et al antivenom is available. As a result, 4. Gutie´rrez JM, Theakston RD, Warrel DA. outcomes in southeastern Nepal. Am J Trop permanent sequelae develop in a num- Confronting the neglected problem of snake Med Hyg. 2004;71(2):234–238. bite envenoming: the need for a global 20. McNamee David. Tackling venomous snake ber of snakebite patients.4 partnership. PLoS Med. 2006;3(6):e150. bites worldwide. Lancet. 2001;357:1680. An experimental study has recently 5. Pinho FM, Zanetta DM, Burdmann EA. 21. Warrell DA. ‘‘To search and study out the shown that the administration of either Acute renal failure after Crotalus durissus secret of tropical diseases by way of experi- the peptidomimetic matrix metalloprotei- snakebite: a prospective survey on 100 pa- ment.’’ Lancet. 2001;358:1983–1988. nase inhibitor batimastat or the chelating tients. Kidney Int. 2005;67:659–667. 22. Lawn JE, Lawn SD. The African challenge. agent EDTA to the subplantar hindpaw 6. Sitprija V. Snakebite nephropathy. Nephrology. Lancet. 2002;359:1527. 2006;11:442–448. 23. Theakston RD, Warrell DA. Crisis in snake region of rats rapidly after venom injec- 7. França FO, Barbaro KC, Fan HW, et al. antivenom supply for Africa. Lancet. tion abrogates hemorrhagic and dermo- Envenoming by Bothrops jararaca in Brazil: 2000;356:2104. necrotic activities of Bothrops asper ven- association between venom antigenaemia and 24. Guidelines for the clinical management of om.29 Rucavado et al suggest that the severity at admission to hospital. Trans R Soc snake bites in the Southeast Asia region. New administration of these drugs at the site of Trop Med Hyg. 2003;97:312–317. Delhi, India: World Health Organization, 8. Ribeiro LA, Jorge MT, Iversson LB. Epidemi- venom inoculation may represent a useful Regional Office for Southeast Asia; 2005. ology of poisonous snake-bites: a study of 25. Johnston F. Tropical health at the top end. An alternative in the neutralization of venom- cases assisted in 1988. Rev Saude Publica. introduction for health practitioners. Darwin, induced local tissue injury. 1995;29(5):380–388. Australia: Top End Division of General 9. Kartthik S, Phadke KD. Snakebite-induced Practice; 2003. acute renal failure. Pediatr Nephrol. 26. Bucaretchi F, Herrera SR, Hyslop S, et al. 2004;19:1053–1054. Snakebites by Bothrops spp in children in CONCLUSION 10. Bucaretchi F, Herrera SR, Hyslop S, et al. Campinas, Saõ Paulo, Brazil. Rev Inst Med Snakebites by Crotalus durissus in children in Trop S Paulo. 2001;43(6):329–333. Snakebite is an underestimated and Campinas, Saõ Paulo, Brazil. Rev Inst Med 27. Wilde H, Bpharm PT, Sitprija V, et al. ignored public health problem that causes Trop S Paulo. 2002;44(3):133–138. Heterologous antisera and antivenins are essen- considerable illness, death, and socioeco- 11. Bucaretchi F, Hyslop S, Vieira RJ, et al. Bites tial biologicals: perspectives on a worldwide nomic hardship to poor populations by coral snakes (Miicrurus spp) in Campinas, crisis. Ann Intern Med. 1996;125(3):233–236. State of Saõ Paulo, Southeastern Brazil. Rev 28. Laing GD, Harrison RA, Theakston RD, et al. living in rural tropical regions of the Inst Med Trop S Paulo. 2006;48(3):141–145. Polyspecific snake antivenom may help in globe where access to life-saving anti- 12. Cupo P, Azevedo-Marques MM, Hering SE. antivenom crisis. BMJ. 2003;326:447. venom is poor. There is an urgent need to Clinical and laboratory features of South 29. Rucavado A, Escalante T, Franceschi A, et al. acquire knowledge of the epidemiology American rattlesnake (Crotalus durissus terrifi- Inhibition of local hemorrhage and dermone- of snakebite envenomation around the cus) envenomation in children. Trans R Soc crosis induced by Bothrops asper snake venom: Trop Med Hyg. 1988;82:924–929. world and to promote public health effectiveness of early in situ administration of 13. Silveira PV, Nishioka SA. South American the peptidomimetic metalloproteinase inhibi- policies directed to improving the treat- rattlesnakebiteinaBrazilianteachinghospital. tor batimastat and the chelating agent Ca- ment and prevention of envenomation. Clinical and epidemiological study of 87 cases, Na2EDTA. Am J Trop Med Hyg. 2000;63(5): with analysis of factors predictive of renal failure. 313–319. Trans R Soc Trop Med Hyg. 1992;86:562–564. 30. Rucavado A, Escalante T, Teixeira CF, et al. 14. Sano-Martins IS, Tomy SC, Campolina D, et Increments in cytoquines and matrix metallo- ACKNOWLEDGMENTS al. Coagulopathy following lethal and non- proteinases in skeletal muscle after injection of We acknowledge Drs Keith Norris and lethal envenoming of humans by the South tissue-damaging toxins from the venom of the Lawrence Agodoa for reviewing the manu- American rattlesnake (Crotalus durissus)in snake Bothrops asper. Mediators Inflamm. script, Ms Laura Hidalgo for support with Brazil. Q J Med. 2001;94:551–559. 2002;11:121–128. literature review, and Mr Gerald Sheehan for 15. Kalantri S, Singh A, Joshi R, et al. Clinical 31. Farsky SH, Gonçalves LR, Gutie´rrez JM, et al. technical support. predictors of in-hospital mortality in patients Bothrops asper snake venom and its metallo- with snake bite: a retrospective study from a proteinase BaP-1 activate the complement REFERENCES rural hospital in central India. Trop Med Int system. Role in leukocyte recruitment. Medi- 1. Ministe´rio da Sau´de, Brasil. Manual de Health. 2006;2(1):22–30. ators Inflamm. 2000;9:213–221. 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