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Snakes of Medical Importance in India: Is the Concept of the “Big 4” Still Relevant and Useful?

      Snakebites continue to be a major medical concern in India. However, there is very little hard evidence of a numerical nature to enable us to understand which species are responsible for mortality and morbidity. For many decades, the concept of the “Big 4” Snakes of Medical Importance has reflected the view that 4 species are responsible for Indian snakebite mortality—the Indian cobra (Naja naja), the common krait (Bungarus caeruleus), the Russell's viper (Daboia russelii) and the saw-scaled viper (Echis carinatus). However, a recent discovery that another species, the hump-nosed pit viper (Hypnale hypnale), is capable of causing lethal envenomation, and that this problem was being concealed by systematic misidentification of this species as the saw-scaled viper, has necessitated a review of the concept of the “Big 4.” The concept of the “Big 4” snakes is reviewed to demonstrate its failure to include all currently known snakes of medical significance in India, and its negative effects related to clinical management of snakebite. The emergence of the hump-nosed pit viper (Hypnale hypnale) as a snake of medical significance has rendered the “Big 4” obsolete in terms of completeness. The concept of the “Big 4” is restricting sound epidemiological work and the development of effective snake antivenoms. It should be replaced by the model introduced in the 1980s by the World Health Organization, which has not received adequate circulation and implementation.

      Key words

      Introduction

      Venomous snakebite continues to be a matter of major medical concern in India, as it has been for at least the last 100 years. In the 1950s, a World Health Organization (WHO) survey estimated the number of bites at 200,000 in India alone with a mortality of 15,000 annually.
      • Swaroop S.
      • Grabb B.
      Snakebite mortality in the world.
      In the late 20th century, the number was estimated at 1.2–2.4 deaths per 100,000, which would equate to a mortality level of 25,000 per annum.
      • Chippaux J-P.
      Snake-bites: Appraisal of the global situation.
      More recent WHO estimates state that the annual mortality due to snakebite in India is approximately 50,000.
      • Warrell D.A.
      WHO/SEARO guidelines for the clinical management of snakebite in the Southeast Asian region.
      There are many causal factors that contribute to this mortality rate. There also remain a great many important, yet unanswered, questions relating to the treatment of snakebite victims. These questions include the correct dosage level of antivenom to be given to a victim with systemic envenomation upon arrival at hospital, the precise nature of snake venoms, including their content and variability, and the lack of reliable means of identifying species of snakes responsible for bites, such as an enzyme-linked immuno sorbent assay (ELISA).
      • Theakston R.D.G.
      • Lloyd-Jones M.J.
      • Reid H.A.
      Mico-ELISA for detecting and assaying snake venom and venom-antibody.
      Much of the information regarding Indian venomous snakes, on which we currently base decisions, has been known for many decades, particularly in respect to the number and geographical ranges of snake species, population densities, and snake habits.
      • Smith M.A.
      The fauna of British India Ceylon and Burma including the whole of the Indo-Chinese sub-region.
      This knowledge has now become accepted wisdom in the field of snakebite and snakebite treatment. There has, however, been very little qualitative herpetological work in India, since the 1940s.

      Original Concept

      One of the widely accepted concepts in Indian snake venom discussions and research is the notion of the so-called “Big 4 Snakes of Medical Importance,” which includes the Russell's viper (Daboia russelii), the saw-scaled viper (Echis carinatus), the Indian or spectacled cobra (Naja naja), and the common krait (Bungarus caeruleus) (Figure 1, Figure 2, Figure 3, Figure 4). These 4 snakes have been believed to cause the vast majority, if not all, fatalities due to snakebite. It was recognised that species such as the king cobra (Ophiophagus hannah) were capable of causing lethal envenoming, but the number of bites and human contact with these other dangerously toxic species ensured that the number of fatalities each year was relatively negligible.
      Figure thumbnail gr1
      Figure 1The Russell's viper (Daboia russelii).
      Figure thumbnail gr2
      Figure 2The saw-scaled viper (Echis carinatus).
      Figure thumbnail gr3
      Figure 3The Indian or spectacled cobra (Naja naja).
      Figure thumbnail gr4
      Figure 4The common krait (Bungarus caeruleus).
      This paper examines the usefulness of the concept of the “Big 4” in light of recent discoveries that other snakes are capable of causing life-threatening envenoming in a significant number of cases. Whether the concept of the “Big Four” is still useful or whether this concept actually causes problems in epidemiology and snake identification is reviewed. Whilst we have largely abandoned antiquated methods of snakebite therapy such as the use of permanganate of potash, chloride of gold, silver nitrate, and the chloride and hypochloride of lime,
      • Wall F.
      The Poisonous Terrestrial Snakes.
      other concepts from that same period, such as the “Big 4,” have remained unexamined.

      Current Situation

      The recent recognition of a snake in India, previously considered essentially harmless, as a species capable of causing life-threatening envenoming brings the value of the concept of the “Big 4” into question. A study in Kerala, India, has established that out of 44 snakes killed and brought to 2 hospitals by snakebite victims from 2000 to 2004, 9 proved to be the hump-nosed pit viper (Hypnale hypnale) (Figure 5).

      Joseph JK, Simpson ID, Menon NCS, et al. First authenticated cases of life-threatening envenoming by the humpnosed pit viper (Hypnale hypnale) in India. Trans R Soc Trop Med Hyg. In press.

      All 9 of these snakes were misidentified by the treating physicians as saw-scaled vipers (E carinatus). This misidentification resulted from the belief that, as the victim was suffering from severe life-threatening envenoming, the offending snake had to be one of the “Big 4” snakes of medical significance. Combining 2 of these cases in which detailed clinical records were available with 3 other subsequently documented H hypnale bites from 2005 revealed the results found in Table 1.

      Joseph JK, Simpson ID, Menon NCS, et al. First authenticated cases of life-threatening envenoming by the humpnosed pit viper (Hypnale hypnale) in India. Trans R Soc Trop Med Hyg. In press.

      Figure thumbnail gr5
      Figure 5The hump-nosed pit viper (Hypnale hypnale).
      Table 1Clinical features of 5 proven hump-nosed pit viper (Hypnale hypnale) bites from Kerala, India
      Table thumbnail fx1
      During prospective data collection in 2005, 88 victims of venomous snakebite with proven systemic envenomation were admitted to the Little Flower Hospital Medical Intensive Care Unit in Kerala.

      Joseph JK, Simpson ID, Menon NCS, et al. First authenticated cases of life-threatening envenoming by the humpnosed pit viper (Hypnale hypnale) in India. Trans R Soc Trop Med Hyg. In press.

      Of these, 8 (9.1%) were proven bites from H hypnale, with the dead snake being brought to the hospital. In another 7 (8%), the victim or bystanders identified H hypnale from a selection of photographs of both venomous and nonvenomous species from the surrounding area. The percentage of bites resulting from H hypnale but not supported by the dead snake or a positive identification by the victim is unknown. Before the study, however, all of these bites would have been recorded as bites by the saw-scaled viper (E carinatus).
      The role of Indian polyvalent antivenom (AV) (an equine product made with N naja, B caeruleus, D russelii, and E carinatus venoms) was evaluated for effectiveness in dealing with bites of H hypnale. The primary criteria for success was restoration of coagulation as measured by the 20-Minute Whole Blood Clotting Test (20 WBCT).
      • Warrell D.A.
      • Davidson N. McD.
      • Greenwood B.M.
      • et al.
      Poisoning by bites of the saw-scaled or carpet viper (Echis carinatus) in Nigeria.
      In the cases of coagulopathy caused by the other local vipers, Russell's viper (D russelii) and the saw-scaled viper (E carinatus), coagulation is normally restored within 18 hours of starting AV. AV is administered at 6-hour intervals, with the victim receiving up to 30 vials in a 12 hour period (ie, 10 vials at T0, 10 vials at T0 + 6 hours, and 10 vials at T0 + 12 hours). The final blood test to establish coagulation is taken at T0 + 18 hours. In the Kerala study 4/5 (90%) of H hypnale cases remained coagulopathic for more than 18 hours despite AV administration,

      Joseph JK, Simpson ID, Menon NCS, et al. First authenticated cases of life-threatening envenoming by the humpnosed pit viper (Hypnale hypnale) in India. Trans R Soc Trop Med Hyg. In press.

      indicating a failure of Indian polyvalent AV to reverse coagulopathic effects of H hypnale venom.
      This conclusion is further supported by evidence from Sri Lanka,
      • Sellahewa K.H.
      • Gunawardena G.
      • Kumararatne M.P.
      Efficacy of antivenom in the treatment of severe local envenomation by the hump nosed viper (Hypnale hypnale).
      ,
      • Premawardena A.P.
      • Seneviratne S.L.
      • Gunatilake S.B.
      • De Silva H.J.
      Excessive fibrinolysis: The coagulopathy following Merrem's hump-nosed viper (Hypnale hypnale) bites.
      which showed that Indian antivenom, the only antivenom available in that country, had very little efficacy in dealing with symptoms of severe local or systemic envenoming by H hypnale. In light of these observations, it is clear that current Indian polyvalent antivenoms have no efficacy against the hump-nosed pit viper, and their use for these bites merely adds risk of allergic sequela, incurs considerable additional cost for terribly indigent victims, and wastes precious resources.
      As a result of the failure of antivenom to restore coagulation, a management protocol has been developed at Little Flower Hospital, whereby antivenom is withheld in proven hump-nosed pit viper bites with systemic envenoming. Treatment consists of conservative management with particular emphasis on monitoring and supporting the indicators of renal performance, such as urine output, and serum creatinine and potassium. We are currently studying the effectiveness of this approach.
      Based on our experience, we have prepared a table (Table 2) outlining the major groups of common clinical findings and responses to treatments encountered during snakebite management in Kerala. The findings related to H hypnale are tabulated alongside those of other snakes of medical significance.
      Table 2Syndromic picture of venomous snakebite in Kerala, India
      Table thumbnail fx2

      Discussion

      The recognition of an additional species of medical importance in India calls into question the usefulness of the concept of the “Big 4.” In the absence of a reliable clinical means of species identification such as an ELISA, the notion of the “Big 4” has led to misidentification in clinical cases with life-threatening signs and symptoms. In victims bitten by hump-nosed pit vipers, victims and physicians can relatively easily rule out cobras, kraits, and Russell's vipers as the offending reptile based on size or markings. The saw-scaled viper, however, has a superficially similar appearance to the hump-nosed pit viper in that it is small and brown. It has, therefore, previously consistently and erroneously been considered responsible for these bites. This was the case even when a simple examination of head scalation on the dead snake by a knowledgeable observer would have revealed the correct identification. The saw-scaled viper possesses multiple small scales across the top of its head (between the eyes), while the hump-nosed pit viper has 5 large plates, including the supraocular, frontal, and parietal plates (Figure 6). There are a number of other species in India, which, like the hump-nosed pit viper, are considered harmless under the old classification scheme. These include the remainder of the pit viper subfamily (Crotalinae), amounting to some 15 species in India, and the coral snake family (Elapidae). Venom research has, for example, shown that the Malabar pit viper (Trimeresurus malabaricus) is capable of causing local necrosis in animals. Whether this species is medically significant to humans needs further study, but it has been recorded as causing 500 bites per annum amongst plantation workers in one hospital in Karnataka alone.
      • Gowda C.D.
      • Rajesh R.
      • Nataraju A.
      • et al.
      Strong myonecrotic activity of Trimeresurus malabaricus venom: role of metallo proteases.
      Urgent work should be undertaken to establish the definitive position of these Indian species in relation to medical significance.
      Figure thumbnail gr6
      Figure 6Comparison of the head scalation of Echis carinatus (a) compared to Hypnale hypnale (b). Note the multiple tiny scales running between the eyes in Echis compared to the large plates in Hypnale.
      The recognition of new species of medical importance also has great significance in the field of snake antivenom design and manufacture. The current Indian polyvalent snake antivenoms, produced by 7 manufacturers, have remained unchanged for many decades. The snake AV producers have argued that their products cover all the snakes of medical significance as defined by the “Big 4.” It has therefore been impossible, to date, to convince them to produce new AVs against the species of emerging medical importance. Some snake AV manufacturers claim para-specific efficacy of polyvalent snake AV against bites of H hypnale.
      • Theakston R.D.G.
      • Warrell D.A.
      Antivenoms: A list of hyperimmune sera currently available for the treatment of envenoming by bites and stings.
      Serum Institute of India snake AV was believed to be effective against bites of this species although doubt has previously been cast on this claim,
      • Warrell D.A.
      Clinical toxicology of snakebite in Asia.
      and the Kerala review adds evidence that there is no para-specific efficacy against H hypnale, as Serum Institute snake AV was used during that study.
      Further, the 4 species mentioned in Indian snake AV product inserts as being covered by these antiserums are N naja, B caeruleus, D russelii, and E carinatus. We know from other research that there are 3 other species of cobra in India, the monocled cobra (Naja kaouthia), the black or Asiatic cobra (Naja oxiana), and the Andaman cobra (Naja sagittifera).
      • Wuster W.
      The cobras of the genus Naja in India.
      The effectiveness of polyvalent snake AV against these other species is unknown. Likewise, the saw-scaled viper of northern India appears to be a separate species (Echis sochureki) from E carinatus,
      • Cherlin V.A.
      Taxonomic revision of the snake genus Echis (Viperidae). II. An analysis of taxonomy and description of new forms [Russian].
      and the effectiveness of standard Indian polyvalent snake AV is not established for this snake.
      Even within a single species, there may be wide geographic variability in the constituent elements of venom. Research has shown, for example, that the phospholipase components may vary widely between northern and southern Indian D russelii.
      • Jayanthi G.P.
      • Gowda T.V.
      Geographical variation in India in the composition and lethal potency of Russell's viper (Vipera russelli) venom.
      Indian snake AVs are all currently manufactured using venoms extracted from snakes (D russelii, E carinatus, N naja, and B caeruleus) captured in a small geographic region of Tamil Nadu in south India. These AVs appear effective in bites occurring in Tamil Nadu by any of these species. The true efficacy of these AVs against specific snakes in other regions, however, requires further study. On a daily basis, doctors proceed on the basis that snake AV is effective against all these regional and species variations, even when there are serious doubts by snake venom experts. The notion of the “Big 4” and its effect on thinking has underpinned this contradiction.
      The notion of the “Big 4” has also obfuscated symptomology. Indian snakebite research generally refers to members of the family Viperidae as generic “vipers.” Little distinction has been made between species as symptoms are often assumed to be identical for both Russell's and saw-scaled vipers. Coagulopathy and renal failure have both been ascribed to these 2 species.
      • Virmani S.K.
      Envenomation syndromes and their management.
      Evidence suggests, however, that Echis species rarely produce renal failure.
      • Warrell D.A.
      • Davidson N. McD.
      • Greenwood B.M.
      • et al.
      Poisoning by bites of the saw-scaled or carpet viper (Echis carinatus) in Nigeria.
      ,
      • Bhat R.N.
      Viperine snake bite poisoning in Jammu.
      Despite this evidence, the belief, propagated by the concept of the “Big 4,” that saw-scaled vipers cause renal failure is still common in India. Many clinicians who hold this view work in areas in which H hypnale, a snake proven to cause renal failure, is found. The assumption that only the “Big 4” are capable of causing life-threatening symptoms has, therefore, led to the saw-scaled viper being wrongly ascribed renal failure as a key feature.
      Treating the “Big 4” as a single and fixed entity by both the antivenom manufacturers and medical professionals is, therefore, giving rise to numerous erroneous assumptions that are negatively impacting patient care.

      Proposed Concept Replacement

      If we are to abandon the concept of the “Big 4,” we need to substitute a more useful classification scheme for the medically important venomous snakes of India. The WHO developed the following methodology in 1981 for the identification of snakes of medical significance:

      Progress in the characterization of venoms and standardization of antivenoms W.H.O. Offset Publ. 1981;58:1–44.

      • Class I—Commonly cause death or serious disability
      • Class II—Uncommonly cause bites but are recorded to cause serious effects (death or local necrosis)
      • Class III—Commonly cause bites but serious effects are very uncommon.
      This methodology is considerably more valuable than the concept of the “Big 4,” particularly in light of the fact that hard, numerical, epidemiological data are not available in India. The WHO mortality figure of 50,000 is itself only an estimate. The numerical contribution of each particular species to these mortality figures is unknown. Therefore, a methodology such as the WHO definition, which provides the ability to assess medical significance without the reliance on specific numbers, is a more useful tool for doctors and medical professionals.
      The following are listed by WHO as Indian Snakes of Medical Importance:

      Progress in the characterization of venoms and standardization of antivenoms W.H.O. Offset Publ. 1981;58:1–44.

      • Class I—Cobra/Russell's Viper/Saw-Scaled Viper
      • Class II—Krait/King Cobra
      • Class III—White Lipped Pit Viper (Trimeresurus albolabris)
      However, on the basis of the WHO definition, we can see that the hump-nosed pit viper satisfies the criteria for joining the list as a class II member, in that it causes both life-threatening symptoms and necrosis.
      When the concept of the “Big 4” snakes of medical importance was developed, it was undoubtedly useful in focusing attention on these 4 species as causes of significant mortality and morbidity in India. However, the recognition of the hump-nosed pit viper as a snake of medical significance, particularly in light of the confusion between this species and the saw-scaled viper, demonstrates the inadequacy of the “Big 4” concept in the current environment. The WHO criteria for listing snakes of medical importance is a much more practical tool as it allows for the possibility that other snakes may yet emerge, following sound epidemiological work, as being medically important.
      Hospitals are a rich source of epidemiological data in respect to snakebite.
      • Viravan C.
      • Looareesuwan S.
      • Kosakarn W.
      • et al.
      A national hospital based survey of snakes responsible for bites in Thailand.
      A significant number of dead species are brought to hospital by the victims, and it is essential that these specimens be preserved in formalin and properly identified by a qualified herpetologist. This will provide sound epidemiological data and positively identify which species are causing morbidity and mortality in a given area. This is a high priority as it directly impacts patient care. If there are species that are currently regarded as harmless, yet are causing morbidity and mortality, it is essential that this be established and that effective antivenoms are developed in order to reduce morbidity and save lives.

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