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Review

NEGLECTED TRC>PICAL DISEASES

Snake Bite in South Asia: A Review Emilie Alirol 1*, Sanjib Kumar Sharma2

, Himmatrao Saluba Bawaskar3, Ulrich Kuch4

, Fran~ois Chappuis1

1 Division of International and Humanitarian Medicine, Geneva University Hospitals, Geneva, Switzerland, 2 B. P. Koirala Institute of Hea lth Sciences. Dharan, Nepal,

3 Bawaskar Hospita l and Research Centre, Ra igad, India, 4 Biod iversity and Climate Research Centre, Frankfurt am Main, Germany

Abstract: Snake bite is one of the most neglected public health issues in poor rural communities living in the tropics. Because of serious misreporting, the true world­wide burden of snake bite is not known. South Asia is the world's most heavily affected region, due to its high population density, widespread agricu ltural activities, numerous venomous snake species and lack of functional snake bite control programs. Despite increasing knowl­edge of snake venoms' composition and mode of action, good understanding of clinical features of envenoming and sufficient production of antivenom by Indian manufacturers, snake bite management remains unsatis­factory in this region. Field diagnostic tests for snake species identification do not exist and treatment mainly relies on the administration of antivenoms that do not cover all of the important venomous snakes of the region. Care-givers need better training and supervision, and national guidelines should be fed by evidence-based data generated by well-designed research studies. Poorly informed rural populations often apply inappropriate first-aid measures and vital time is lost before the victim is transported to a treatment centre, where cost of treatment can constitute an add itional hurdle. The deficiency of snake bite management in South Asia is multi-causal and requires joint collaborative efforts from researchers, antivenom manufacturers, policy makers, public health authorities and international funders.

Introduction

Since ancient times, snakes have been worshipped, fea red, or loatJ1cd in South J\sia. Cobras appear in many tales and myths and arc regarded as sacred by both Hindus and Buddhists. Unfortuna tely, snakes remain a pa inli.d rea lity in the da ily li fe of mil lions of villagers in this region. Indeed, although antivcnom is produced in sufficient quantities by severa l public and private manufacturers, most snake bite victims don 't have access to quali ty care, and in many countries, both morbidity and mortality clue to snake bites arc high . T he neglected status of snake bite envenoming has rcccntJy been challenged [! ] but as outJinccl below, apart from tJ1e production of' antivenom, snake bite envenoming in Souili J\sia shares all ilie characteristics of a neglected tropical disease. T his review aims a t summarizing and discussing tJ1e epidemiology, cl inical features, diagnosis, and treatment of snake bite envenoming in South J\sia (Bangladesh, Bhutan, India, Nepal, Pakistan, and Sri Lanka) .

Methodology

Articles were identi fied by searching Mccl linc through PubMccl using various combinations of terms including "snake," "snake bite," "envenoming," and "venom." Research papers and case reports from Ba ngladesh, Bhutan, India, Nepal, Pakistan, and Sri Lanka were retrieved, as were significant papers from other Asian

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countries. J\clditional articles were obtained by citatio n tracking of' review and original articles. The review also drew 0.11 conference proceedings and original research concluctecl by the authors.

Epidemiology

J\n accurate measure of' the globa l burden o f' snakebi te envenoming remains elusive despite several attempts to estimate it and, apart from a few countries, reliable figures o n incidence, morbidity, and mortality arc scarce [2-4] . South J\sia is by far the most a flectccl region [2,4]. India has the highest nwnbcr of' clcatJ1s clue to snake bites in ilic world with 35,000- 50,000 JJcoplc dying per year accord ing to World Health Organiza tion (',\/HO) direst estimates [2,4]. In Pakistan, 40,000 bites arc repor ted annuall y, which result in up to 8,200 fatalities [4,5] . In Nepal , more th an 20,000 cases of' envenoming occur each year, with 1,000 rccorclccl deaths [6]. In Sri Lanka, around 33,000 envenome d snake bite victims arc reported annually from government hosp ita ls [4-,7]. J\ postal survey conducted in 2 l of' the 65 adm inistrative districts of Bangladesh estimated an annual incidence o f' 4.3 per I 00,000 population and a case fata lity of' 20% [8] . However, existing epidemiological data remain fragmented and the true impact of' snake bites is very likely to be underestimated. Surveys in rural Sri Lanka showed iliat hospital data record less then half o f' the deaths clue to snakebite [9- 1 I]. In Nepal, a review of district hospital records showed that national figures underestimated t he incidence of snake bite by one order of magnitude [ I 2] . The highest figures reported in J\sia so far come from a commun ity-based survey concluctccl in southcast Nepal in 2002, which revealed annual incidence and mortality rates of I , 162/ l 00,000 and 162/ l 00,000, respectively [1 3]. Figures o f' a similar magnitude were recently also obtained in a nation-wide commun ity-based survey in Bangladesh (M. R . Ral1man, personal communication).

Snake bite is an important occupational injury a ffecting fa rmers, plantation workers, herders, and fi shermen. Open-style habitation and the practice of sleeping on the floor also expose people to bites from nocturnal snakes . J\s summarized in Table l , severa l epidemiological studies have outl ined characteristics of snake bite

Citation: Alirol E, Sharma SK, Bawaskar HS, Kuch U, Chappuis F (201 OJ Snake Bite in South Asia: A Review. PLoS Negl Trap Dis 4(1): e603. doi:10.137 1/ journa l.pntd.0000603

Editor: Janaka de Silva, Faculty of Medicine, University of Kelaniya, Sri Lanka

Published January 26, 2010

Copyright: «:> 2010 Alirol et al. Th is is an open-access article distributed under the terms of the Creative Commons Attribut ion Li cense, w hich permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: The work of UK is supported by the LOEWE Programme of the State Government of Hessen, Germany and by the Wellcome Trust (Research gran t GR079027MA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests: The authors have declared that no competing interests exist.

• E-mail : emilie.aliro l@hcuge.ch

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Table 1. Characteristics of snake bite victims in South Asia.

Characteristic Details References

Age The mean age of snake bite victims is around 30 years. Three-quarters of the victims [7,9, 12, 14, 1S,22,37,40,49,55,56,76,88,89,93,94,97, 104, 111 - 119] are in the 10- to 40-year age group, broadly in agreement with demography.

Gender There is a clear preponderance of males among snake bite victim s. A 2:1 male [7,9, 12,14,15,22,37,40,49,55,56,76,88,89,93,94,97. 104,111 - 119] to fema le ratio is frequently observed.

Occupation Farmers account for more than half of the victims. Students and housewives [9, 13, 15,22,40,56,93, 114,117,120] are also frequently bitten.

Time of bite The time of bite depends on the relative abundance of diurnal and nocturnal [7,9, 12, 14,15,22,37,49,56,88,89,94,97, 104, 114- 11 71 snakes. Krait bites generally occur at night, whereas viper and cobra bites most ly occur during daytime.

Site of bite 60%-80% of bites occur on the foot, ankle, or leg. Bites on the head and trunk [7,9,12,14,15,22,40,49,56,76,77,88,93,97,104,114- 118,121,122] are mostly due to nocturnal species biting sleeping people.

Delay between bite and treatment

The bite-to-treatment delay varies greatly, rang ing from 30 minutes to 15 days. [7, 12, 14, 15,22,40,49,55,56,74,88,93,94, 104, 113- 11 9, 121 J Most studies show that at least 60% of victims reach a health centre with in six hours but very few in less than one hour.

First aid methods

In eight out of 15 studies, more than 50% of snake bite victims used inappropriate [7,9, 13,22,40,49,74,76,88,93,104,113,115- 117,1 19]) and harmful first aid methods. Tourniquets are used by up to 98% of patients.

Mortality Morta lity rates are highly variable, ranging from 0.5% to 58%. Most fata li ties [7,9, 12- 15,22,37,49,55,56,76,88,89,93,94,97, 104, 1 11, 113- 121] occur before reaching treatment centres.

doi:10.1371 /journal.pntd.0000603.t00l

victims in the region. Bites arc more frequent in young men, and generally occur on lower limbs. The incidence of snake bites is higher during the rainy season and during periods of' intense agricultural activity (1 4, 15). Snake bite incidence and mortality also increase sha1vly during extreme weather events such as floods. During the 2007 monsoon flood disaster in Bangladesh, snake bite was the second most common cause of death, after drowning, eclipsing morta lity from diarrhcal and respi ratory diseases and illustrating how important snake bite can be in this region compared to other health problems [ 16].

Venomous Snakes in South Asia

The number of' diflcrcnt snake species found south of the Himalayas is estimated to be around 300, including about 67 front-fanged venomous species of the families Elapidac and Vipcridac [17- 21).

Viperid snakes arc represented by 26 species belonging to the true vipers (subfamily Vipcrinac) and pit vipers (Crota linac). J\mong the true vipers, Russell 's viper (Daboia russelii) is associated with the highest morbidity and mortality . In Anuradhapura District, Sri Lanka, up to 73 % of' all admitted snake bites arc attributed to this species [22] whose distribution extends north to the lndus valley of Pakistan and K ashmir, to the foothills of' the Himalayas in Nepal and Bhutan and to Bangladesh in the cast. Saw-scaled vipers (Echis cminatus and E. soc/wreki) arc other very important vipcrinc species that inhabit open and dry environ­ments. E. sochureki causes numerous bites in northern India and has long been regarded as one of' Pakistan's deadlies t snakes [I 7,23] ; E. cminatus is regionally highly abundant and causes many bi tes in parts of western and southern India [ l 8] and in arid coastal areas of' northern Sri Lanka [24]. Three other species of' trnc vipers that occur in the wes t of' South J\sia arc the Levan tine viper (i\llacrov1jJe1-a lebetina) and two species of desert vipers (E1isticophis macmalwni and Pseudocerastes persicus) . Although their bites have been considered to be comparatively rare, they arc capable of' causing severe envenoming [25,26].

Pit vipers belonging to various genera [27 ,28] have traditionally been regarded as being of' lesser concern in South J\sia. However,

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these snakes occur in most habitat types from mang r oves to the high mountains, and some species arc common in gardens and agricultural landscapes. Envenoming by green pit vipers is very common in wide regions of' Bangladesh and Nepal [I 2,29] , and bites by the mountain pit viper (Ovoj;his monticola) occ ur in Nepal where it is the most frequently encountered venom o us snake at altitudes of' 900- 2, 700 m [2 l ,30]. Although causing fe w fatalities, bites by these species produce marked local cflccts th a t can result in chronic conditions and permanent scquclac [3 l ,32). In southern India, recent studies have reported massive morbidity among plantation workers due to bites by a much sma lle r species, the Malabar pit viper (Tiimeresums malabaiicus) [33]. Hump-nosed pit vipers (Hy/male hyjmale and H. nepa) arc also e merging as medically important species in the region , and can cause renal failure and haemostatic dysfunctions [34,35). Several fatali ties due to H. hyjmale envenoming, for which there is no specific antivcnom , were reported in India and Sri Lanka [34,36,37] .

The family Elapidac is represented by at least I 7 terrestrial species (including cobras, king cobras, kraits, and coral snakes) and numerous species of' sca snakes in South Asia. Bites by cobras (Nqja species), which arc best known for raising their head a nd anterior body and spreading their neck as a hood in defence, ty pically occur outdoors in the late ali.crnoon [I 7,18]. The spectacled cobra (Nqja nqja), one of' India 's commonest snakes, causes numerous cases of' envenoming every year [38] . In ohc nonhcrn and eastern parts of th Indian subcontinent, the monoccllatc cobra (N kaoulhia) also belongs to the medica lly important sna kes. J\ th ird cobra species, N oxiana, occurs in the northwcst [18,20,2 1). Kraits (Bungarns species) arc slender, nocturnal snakes that often enter human dwellings at night in search of' prey. Consequently, many victims of' krait bites arc bitten while asleep. Case fata lity rates of' krait envenoming reach up to 77%- 100% without treatment [1 7,39] . Traditionally, most krait bites in South Asia have been attributed to the common krait (Bungarus caernleus) , however, in South J\sia alone there arc eight species of' Bungams, several of' which arc morphologica lly similar to B. caemleus. Several studies have demonstrated that a number of these arc medically important in the region [40--43] . Coral snakes arc smaller elapid snake species that arc brightly coloured. They arc rarely encountered by

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humans and thus arc thought to cause few bites, but fa talities have been reported [4-4] . Sea snakes arc large, paddle-tailed and primarily marine snakes that Iced on fish and fish eggs. They arc often caught in the nets of fi shermen who arc a t risk or bites while handling them. Most fatalities following sea snake bites arc attributed to Enhy d1ina schistosa [45] but the species identity of sea snakes involved in bites in South Asia has only very rarely been es tablished [46,47].

An often overlooked problem is that or nonvcnomous or mildly venomous species. They represent the vast majority of living snakes, and may be mistaken for venomous snakes and / or involved in snake bite in South Asia. Rat snakes (P?)!as species, Coelognathus species) arc large, rapidly moving snakes that arc often conli.iscd with cobras. Most notoriously, several genera of small nonvcnomous snakes share the same colour pattern as kraits [1 9,48]. Wolf snakes (Lycodon species) arc of particular concern in th is regard because some of them (e.g., Lycodon aulicus) arc vc1y common inside and around houses and bite aggressively if disturbed [ 40].

This species diversity has a significant public health impact: in addition to increasing the risk of bites in all kinds of environments, it complicates clinical management with respect to both diagnosis and treatment, as well as antivcnom design and manufacture and control strategics.

Clinical Features of Snake Bite Envenoming

A widespread belief is that snake bites inevitably result in envenoming. H owever, bites by nonvcnomous snakes arc common and bites by venomous species arc not a lways accompanied by the injection of venom (9ry bites). large survcy_ conductcd in ten hospitals of southern Nepal revealed that envenom ing occurred in only 10% ofth victimJ; [12]. ln Kcrala, India, only 2 19 out or 635 pati nts (34-%) with proven snake bit dcvolopccl signs of systemic envenoming [4-9]. Likewise, in Bangladesh the proportion or noncnvcnomcd bites reported in hospital-based studies varied between 60 % and 80% [29,50]. Moreover, as symptoms associated with panic or stress sometimes mimic earl y envenoming symptoms, clinicians may have diflicultics in determining whether envenoming occurred or not.

When envenoming docs occur, it can be rapidly life-threatening. Snake venom is a complex mixture of toxins and enzymes, each of which may be responsible for one or more distinct toxic actions. In bites by South Asian vipcrid snakes, envenoming results in local pain and tissue damage, charactcrisccl by swclJing, blistering, bleeding, and necrosis at the bite site, sometimes extend ing to the whole limb [l 7] . Vipcrid venoms can also induce coagulopathy and platelet dysfunction , leading to spontaneous systemic haemorrhages and persistent bleeding from fang marks, wounds, or gums (Figure I). Intracranial bleeding, including anterior pituitary haemorrhage, and multi-organ fa ilure arc common causes of death [51]. A prospective study conducted in Anuradhapura District, Sri Lanka, showed that 92% of patients with Russell 's viper envenoming presented with local swelling and 77 % had haemostatic disturbances [7]. In addition, Russell 's viper can cause acute renal fa ilure and ncurotoxicity, as has been shown in several studies conducted in south India and Sri Lanka [7 ,22,49,52].

Among the E lapiclac, bites by N. 111ya and N. kaouthia can cause significant local swelling and sometimes extensive tissu necrosis or the bitten limb [31 ,38;53] , whereas bites by kraits or sea snakes do not usually cause signs of loca l envenoming and can be virtually painless. Cobra venom contains mainly postsynaptic ncurotoxins, which bind and block acctylcholinc receptors of the neuromuscu­lar junction, while krait venom in addition contains prcsynaptic

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' .. - , -.

I~ " . • ,,. - .. I, • • . ·~• • - -"' ......,__

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Figure 1. Gum bleeding after bite by Russell's viper. In Asia, coagulation defects and spontaneous bleeding are characteristic of bites by viperid snakes and are caused by procoagulant and haemorrhagic toxins in the snake venom. Image credit: D. A. Warrell. doi:10. 1371 /journal.pntd.0000603.g001

tox ins that damage nerve endings [54]. Progrcssiv clcse;cnding paralysis is the hallmark of systemic-envenoming by clapicl snakes in South /\&ia (Figure 2). Ex Lrao ular muscles arc panicularly sensitive to nGuromuscular blockade, Jcacling to a cli:-oop of upper eyelids Q)ilatcra l ptosis), a li-cqucntly ohs rvcd arly sign or paralysis [55] . Patients arc ofi:.c.n unabl to protrucl their tongue beyond th incisors and may present wiJh difficulty speaking or swallowing. Limb weakness, loss of clcc.p tendon re fl exes, and fi xed dilated pupils may follow. Once paralysis reaches th.c diaphragm a nd the intcrcostal muscles, victims usual! die o f respiratory failur iJ they arc not adequately ventila ted . Hospita l- based studies in Sri Lanka showed th at 48 %- 64-% or B. rnern/eus victims dcvclopccl rcspirato1y paralysis and required mecha nical ventila­tion [1 5,56]. Although many clinical signs o f ncurotoxic­envenoming by cobras and kraits arc similar, with both genera able. to cause respiratory failure within 30 minutes of the bite [5 7,58] , krait bite envenoming is often associated with a delayed onset and prolonged total period of paralysis. This is clue to the fi.in ction and effects or the most lethal components of krait venoms, bcta-bungarotoxins, which des troy nerve terminals [59). While coagulopathy and bleeding arc common fea tures or envenoming by certain clapicl snakes in Austra lia and New Guinea [60], clinical bleeding and clott ing problems have not been reported alter bites by South Asian clapicls. Likewise, systemic myotoxieity fo llowing elapicl snake bites was previously known only from sea snakes a nd some of their terrestrial relatives in Australia and New Guinea [60]. However, vcnom-inclucccl gcncralizccl rhabclomyolysis and renal fa ilure has recently also been observed in envenoming by the greater black krait (B. nige1) in Bangladesh, fi.uthcr complicating clinical management (Faiz et al. , unpublished data) .

Diagnosis

T he identifica tion or snake species is crucial for optimal clinical management, because it allows clinicians to choose the appropri­a te treatment, anticipate complications, and therefore to improve prognosis. ]Vforcovcr, as specific antivcnoms arc not available for South Asian pit vipers and most krait species, identify ing these species would help to avoid wasting this expensive treatment and exposing patients to antivcnom-incluccd adverse reactions. As mentioned above, bites by nonvenomous species arc common and may throw clinicians in to conli.1sion.

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Figure 2. "Broken neck" sign observed in a 14-year-old girl bitten by a Russell's viper in India. Envenoming by cobras, kra its and-in some areas-by Russell's viper freq uently leads to progressive descending paralysis. Looking for the broken neck sign, which is caused by paralysis of the neck flexor muscles, should be part of the routine cli nical assessment of patients. In this case, neuroparalysis persisted for five days despite antivenom treatment, but without progression toward respiratory fa il ure. Image credit: H. S. Bawaskar. doi:10. 1371/journal.pntd.0000603.g002

Unfortunately, in many cases the biting snake is not seen, and if it is, its description by the victim is often misleading [40] . Even when the dead snake is brought to the hca ltJ1 centre, misidenti­fication is common. For example, hump-nosed pit vipers (H. lryjmale) arc frequently misidentified as saw-scale vipers (E. carinatus) in Kcrala , India [34] . Consequently, many H. lrypna/e bite victims encl up receiving incflcctivc an tivcnom. Throughout South Asia, krait bites arc routinely attributed to B. cae111/eus based on cl in ical syndromes and the great superficial similarity of B. caemleus, B. si11danus, and B. walli. However, envenoming by krait species other than B. caeruleus that docs not respond to available antivcnoms may be common , as observed in Bangladesh (Faiz et a l. , unpublished data; Kuch et al ., unpublished data).

Most physicians in South Asia have to rely on tl1c circumstances of the bite and the clinical features of envenoming to infer the biting species. Coagulopathy, when present, is diagnostic of viper and pit viper bites in Soutl1 Asia and can be observed using the 20-minutc whole blood clotting test [61] . In Sri Lanka, B. 1:aemleus envenoming has a characteristic cpidcmiologic and clinical pattern [15). Syndromic approaches have been proposed to assist physicians in identifying the biting species [6 1] and attempts have been made to develop clinical scores based on envenoming

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featu res [62]. However, careful studies of cnvcnomir:ig profiles a rc lacking for most species in th is region. T hus, more cli.~nical research using reliably identified snakes is needed to fi.1 .-thcr explore cliflcrcnccs in envenoming syndromes between aclcli ional species, a nd to evaluate their applied utility .

Immunoassays for detecting venom antigens in bocly fluids have been described for a number of species [63- 65] , and .a ttempts have been made to develop ELISA tests for South J'\sia [66- 68] . Unfortunately, a narrow focus on an insufficient nu1n bcr of species and cross-reactivity between venoms has so far J1 indcrccl the development of a reliable diagnostic test [64,69]. To limit the problem of cross-reactivity, the use of purified species-specific toxins for immunization or aflinity -purificcl v.::nom-spccific polyclonal antibod ies may be worth considering [7 ()]. However, even then the paucity of reliable data on the c livcrsity a nd distribution of venomous snakes in South Asia, the 11.111availability of venom for almost all of the species, and the very li mited insight into venom variability even witl1in the commonest species- a ll caused or promoted by restrictive wi ldlife legisla t ion- remain major obstacles for tl1c design and production of imrnunodiagnos­tics. Under tl1csc aspects, the use of forensic molecula r techn iques as an explorativc and complementary tool for s nake species diagnosis is promising. Forensic routine has shown that it is feasible to identify an aggressor (e .g., human or d og) based on trace DNA from bite marks [7 1], and this is also possible in the case of snakes [72] . PCR amplification and sequenc ing of" snake DNA obtained from bite-site swabs has recently been used to identify biting snakes in an an imal model and in clinical cases from Bangladesh and Nepal (Kuch et a l. , unpublished data). The util ity of this method as a clinical diagnostic tool , however, awaits further study.

Management of Snake Bite Victims and Recommended Treatment

H ealth workers in ru ra l districts arc usually poorly tra ined to manage snake bite envenoming, which is a complex e mergency. A recent survey conducted in India and Pakistan showed that many doctors were unable to recognize systemic signs of envenoming [73] . Another study in northwcst India revealed that most snake bite victims presenting at primary health centres received inadequate closes of antivcnom and that out of" 'l-2 p a tients who required assisted ventilation, only one was intubated [74]. Improving the knowledge of care-givers at all levels o f the health system is a challenge of paramount importance and g reat urgency in South Asia. Papua New Guinea, where snake bite management training programmes have been implemented in both rural and urban hospitals, could serve as an inspiring model in th is regard.

First aid fost experts agree Ulat snako bite victims should be fran sportcd

as quickly as possible to a medical centre. whcr they can be cl in:ica ll y evaluated by qua lified medical stafl ; and where antivonoms arc ava ilable. In fact , tim of transport ,-vas shown to b a.crucial d tcrminant of snake bit mortality in eas tern Nepal [ I 3], and studies in southern India confirmed that delayed anrivcnom administration was associated with an incrrasQd risk or complica tions [49, 75). The bite vjctim should b reassured, the bi Qcn limb immobilized with a makeshift splint or sling, and the pa tient transported. vValking is contraindicated, beca use muscula r contractions romott venom absorption.

These simple recommendations arc unfortunately rarely fo llowed and vi tal time is often lost. The majority o f" victims first report to trad itional healers [! 0,40,55, 76]. Popular traditional

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treatments include chanting, incisions, attempts to suck venom from the bite site, and the applica tion of herbal medicine or snake stones. Two studies in Nepal and Bangladesh showed that 90% and 98% of snake bite victims, respectively, used tourn iquets (Figure 3) [4-0,77). In Bangladesh, incisions at and around the bite site were made in 28% of envenomed victims and in l3%- l4% of those without signs of envenoming [40). In northwcst India, incision and drainage were practiccd by 20% of patients [74]. These trad itional measures arc strongly contraindicated as they arc ineflcctivc and in most cases deleterious. For example, tourniquets cannot be safely left on for long without risking severe local damage including ischcmia, necrosis, and gangrene [78, 79].

lfn 1979, Sutherland et .i i. recommended th e; prcssurc­imrndbilization method as an cfl" ctiv alternative first a id method L80]. According to the authors, the bitten limb should be bound firmly with a crepe bandage, starting dista lly around the toes or fingers and moving proxim ally. Although this technique has been extensively promoted in Australia , its cllicacy remains controversial [81). For example, a rece nt study in Austra lia showed that crepe bandages ra rely ge nera ted optima l pressures compared with elasticized bandages [82]. In a study in India, pressure- immobiliza tion was found to be difficul t to apply correctly despite intense previous training of care providers [83] . In the Australian study, training did improve participants' ability

Figure 3. Tourniquet on a 43-year-old woman presenting at a rural health post in Nepal. First-aid methods applied throughout South Asia are large ly inadequate. Tourniquets in particular can have deleterious effects. This patient consulted after being bitten by a nonvenomous rat snake (Ptyas mucosa) that she had killed and brought for identification. After reassurance, local treatment, and observation, she was uneventfully discharged from the health post. Image credit: E. Alirol. doi:10. 1371 /journal.pntd.0000603.g003

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to apply elasticized bandages [82), and in a study ii.n Papua New Guinea, participants living in an area where sn.a kc bites arc common were very successful in ga ining and rctain.i ng the ability of correctly applying pressure-immobilization ( D . Williams, personal communication). T his nicthod i$, howcv r, contraindi­di tctl for vipc · and cobra bites as it may increase loca l ti ssue damage [8 1,84.J and may contribute to delaying trc1nsport of the victim to a treatm ent centre.

Antivenoms Immunothcrapy is the only specific treatment or snake bite

envenoming. Antivenoms arc produced by fractiona l:ion of plasma obtained from immunized animals, usua lly horses [85). T hey can be either monovalcnt or polyvalent, depending on t:l1c number of species (single or multiple, respectively) whose venoms arc used for immuniza tion. Al though monovalent antivcnom h ce1s ofi.cn been considered more cllicacious, the production o f polyva lcnt antivcnom is preferred in many coun tries as s nake species identifica tion is general ly not possible for the attending physician. Antivcnoms have been ava ilable in South Asia for the past 60 yea rs, and all existing products arc manufactur d by Indian companies. Traditiona lly, the production has focused on four species believed to be responsible for most dea tli. s: .N naja, B. caeruleus, D. russelii, and E. carinatus. H owever, a number of other species that contribute to morbidity and morta lity in tl1c region have not been considered, and envenoming by tl1csc species usua lly docs not respond adequately to existing antivcnoms [34-,36).

The success of antivcnom therapy depends on the ab ility of immunoglobulins to bind, extract, and eliminate toxins present in the body. While their eflicacy in restoring hae mostasis and cardiovascular fimctions is well es tab lished, the ability of antivcnoms to prevent tissue damage and to reverse ncurotoxicity is more controversial [56,86,87). For instance, administra tion of antivcnom to krait bite victims with es tablished respiratory paralysis docs no t reverse paralysis [55 ,86,87). T his lack of cl inica l cllectivcncss often contributes to the administration of excessive amounts ofantivcnom [88,89] . Moreover, treatment outcome can vary greatly witl1 the geographical area as tl1c venom composition and antigenic properties of toxins can be highly varia b lc across the range of a given snake species [90,9 I] . Indian an tivcnoms arc produced using venoms from snakes captured in a tiny geographic area of the Sta te of Tamil Nadu, and may there fore be less cflectivc in other regions [92). For example, the cllicacy of Indian polyvalcnt antivcnoms for the trea tment of envenoming by Russell 's viper in Sri Lanka is controversial [22,93).

/\s a matter of fact, most of the antivcnoms that a rc routinely used in South Asia have never been su~j cctcd to independent preclinical testing and formal evaluation in clinical tria ls. Their cflicacy and safety profiles have not been properly esta blished, and there is currently no evidence-based protocol for their adminis­tration and dosage. Up to 80% of patients treated with Indian antivenoms present one or more adverse cflec t(s) such as anaphylactoid or pyrogcnic reactions, or late scrum sickness [37 ,93,94). While to our knowledge no fatal cases have been reported in South Asia, severe drug reactions occur a nd arc likely to be under-reported . Adverse reactions can be efficiently managed by cheap, widely available drugs (e .g. antihistaminics, corticoids, adrenalin), but their prophylactic use yielded comra­dictory results [94- 96] . T he risk of severe adverse events exists but must be balanced against the life-saving potentia l of this trea tment.

Antivcnoms may be supplied free of cos t by some ministries of health but their supply remains insuflicicnt and irregular in several countries [I 2] , leading to tl1c purchase of drugs by the patients'

January 2010 I Volume 4 I Issue 1 I e603

Box 1. Key Learning Points

• South Asia has the highest incidence and mortality rates of snake bite in the world.

• Bites by venomous snakes in this region can cause local t issue damage, neuroparalysis, systemic haemorrhages, generalized myotoxicity, acute renal fail ure, or complex combinations of these.

• Recommended first aid measures include reassurance of the snake bite victim, immobilization of the bitten limb, and rapid transport to a competent treatment centre.

• Antivenom is the only specific treatment for snake bite envenoming, but existing products cover only a very limited number of medically significant species.

relatives. O ne vial or antivcnom of'Indian production costs around US$8- 10, which is equivalent to several days of salary for poor farmers. T hus, many cannot afford to purchase the average I0- l 5 vials needed to reverse envenoming [97] .

Ancillary treatment T he management ol' cnvcnomccl snake bites is not limited to the

administration of' antivcnoms. In the case of ncurotoxic enven­oming, artificial ventilation and careful airway management arc crucial to avoid asphyxiation in patients with respiratory paralysis. Cases of complete recovery from severe neuromuscu lar paralysis without antivcnom have been reported after prolonged artificial ventilation [98].

J\nticholincstcrasc drugs such as cdrophonium can partly overcome blockade by postsynaptic ncurotoxins and have shown good efficacy in cobra bite envenom ing [6 1,99]. J\ few cases of succcssfi.tl anticholin cstcrasc use have also been reported in krait bite envenoming in India [ 100], bu t there is cu rrently no trea tment to stop the destruction of nerve endings by p rcsynaptic kra it toxins once this dege neration process has started.

Box 2. Five Key Papers in the Field

1. Kasturiratne A, Wickremasinghe AR, de Silva N, Guna­wardena NK, Pathmeswaran A, et al. (2008) The global burden of snakebite: A literature analysis and modelling based on regional estimates of envenoming and deaths. PLoS Med 5: e218. doi:10.1371/journal.pmed.0050218

2. Warrell DA (1999) WHO Guidelines for the clinical management of snake bites in the South East Asia Region. SE Asian J Trap Med Publ Health 30: 1-83.

3. World Health Organization (2007) Rabies and envenom­ings: A neglected public health issue. Geneva: WHO. Available at http://www.who.int/bloodproducts/animal_ sera/rabies_envenomings/en/index.html

4. Ariaratnam CA, Thuraisingam V, Kularatne SA, Sheriff MH, Theakston RD, et al. (2008) Frequent and potentially fatal envenoming by hump-nosed pit vipers (Hypna/e hypna/e and H. nepa) in Sri Lanka: Lack of effective antivenom. Trans R Soc Trap Med Hyg 102: 1120- 1126.

5. Gutierrez JM, Theakston RDG, Warrell DA (2006) Con­fronting the neglected problem of snake bite envenom­ing: The need for a global partnership. PLoS Med 3: el 50. doi:10.1371/journal.pmed.0030150

·."(®.·. www.plosntds.org 6

Box 3: Main Challenges

(1) Improving access Access to care is hindered both by the rem oteness of snake bite- prone areas and by the cost of snake bite management. A community survey in Nepal showed that snake bite envenoming represents a substant1 al financial burden for rural households (13]. Despite the n,ushroom­ing of well-equipped private clinics in some ru .-al areas of India, poor villagers rarely have access to l'Tlechanical ventilation or dialysis. (2) Improving clinical management Simple and standardized protocols on snake bit:e manage­ment are needed. Despite the publication of regional guiding principles (61], national protocols are not always consistent with each other (e.g., low initiail dose of antivenom advised in Nepal versus high initi al dose in India and Bangladesh), are often not available in peripheral health structures and are poorly explained to end users. Moreover, manufacturers' recommendations are often misleading (107]. In Nepal, the application of different protocols may play a role in the wide range (3<>/o-58%) of case-fatality rates reported from various hospita ls (1 2]. (3) Improving diagnostic and treatment tools The lack of field-applicable diagnostic tools to identify snake species contributes to poor case definit ions [11 OJ, mismanagement of patients, and uncertaint ies about snake bite epidemiology. Snake bite victims in South Asia are stil l reliant on old generations of antivenoms, and several venomous species are not covered by exist ing products (92]. The pharmacokinetic and pharmacodynamic properties, efficacy, and safety of most Indian a ntivenoms have never been studied or compared. WHO has recently endorsed the strengthening of antivenom production, and efforts are being made to help Indian manufacturers to improve the quality of existing products (108] . However, the impact of this approach on the cost of antivenom production needs to be carefully anticipated and closely monitored (1]. (4) Improving knowledge Improving the knowledge of both care-givers and rural communities is crucial. Health workers in rural districts are usually poorly trained to deal with this complex emergen­cy. For example, many doctors in India and Pakistan appear to be unaware of the criteria for antivenom administration (73]. Education of rural commun ities on snake bite, avoidance of useless or dangerous first-aid measures, and the importance of rapid transport of victims to treatment centres should be widely implemented (13].

Bacterial infect ions can develop at the bite site , especiall y if the wou nd has been incised or tampered with nonstcri lc instruments, and may require antibiotic treatment. H owever, there arc currently no data supporting their systcma Li use [1 0 1]. J\ booster close of tetanus toxo icl should be administered but only in the absence of' coagulopathy [l 7]. Necrosis on the bitten limb may require surgery and skin grafts, particularly in the case or cobra bites. ff necro tic tissues arc not removed, secondary bacterial infections can occur [53]. Tensed swel ling, pale and cold skin witl1 severe pain may suggest increased intracompartmcntal pressure in the a.fTcctccl limb. However, fasc iotomy is ra rely justified. In particular, it can be disastrous when performed before coagulation has been restored. J\ clear proof of significant compartment syndrome by measurement of substantially clcvatccl intracompart­mcntal pressures is a prerequ isite [61].

January 2010 I Volume 4 I Issue 1 I e603

Control and Prevention

In practice, strategics to contro l snake populations and to prevent snake bites arc noncxistcnt in South Asian coun tries. Many bites could be avoided by educating the population at risk. Sleeping on a cot (rather than on the floor) and under bed nets decreases the risk of nocturnal bites in Nepal (55, I 02). Rubbish, termite mounds, and firewood, which attract snakes, can be removed from the vicin ity of human dwellings. Attempts can be made to prevent the proliferation or rodents in the domestic and pcridomcstic area. Thatched roofs, and mud and straw walls arc favoured hiding places for snakes and should be checked frequently. Many bites occur when people walking barefoot or wearing only sandals accidental ly step on a snake. Using a torch/ llashlight while walking on footpaths at night, and wearing boots [ !03) and long trousers during agricultural activities, could significantly reduce the incidence of bites.

A complementary strategy is to decrease the risk or dying from envenoming snake bites. Many areas where snake bite envenom­ing occurs arc relatively in access ible by road, especially during the rainy season, and transport to a health centre sometimes takes

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(Daboia msselii msselii) bite in J\nuradhapura, Sri Lanka: a prospective study of 336 pm ients. Southcast Asia n J Trop Med Public I lealth 34: 855-862.

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·_"i:tii'J_: www.plosntds.org .. 7

more than 24 hours (14,74-,104). In Nepal, a progra1rnmc for rapid transport or snake bite victims by motorcycle volunteers to a specialized treatment centre significantly reduced the risk of faLal outcome (Sharma et al. , man uscript in preparation .

Conclusion

While sub-Saharan i\frica faces a dramatic crisis in antivcnom production and supply (LOS, I 06] , shortage or antivcIJom is not the most pressing issue in Soutl1 J\sia. Indeed, it is cstima Lcd that [nd ia produces around one million vials or antivcnom each year [107). Despite these large volumes or production, sever al chall enges persist that prevent appropriate management or sna.l,;c bite victims in South Asia. Poor access to often inadequately e quipped and sta flcd medical centres in rural areas, high cost of tr eatment, and inadequate use or antivcnoms arc major conccn, s (1 08, 109). In creased attention and means should be dedica ted to snake bite envenoming by researchers, fimding agencies, pliarmaccutical industries, public health authorities, and supranational organisa­tions, as all have contributed to keeping this important public health problem a truly neglected disease.

23.

2+.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34 .

35.

36.

37.

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39.

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January 2010 I Volume 4 I Issue 1 I e603