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Hump-nosed viper bite: an important but under-recognized cause of systemic envenoming

Abstract

Hump-nosed viper bites are common in the Indian subcontinent. In the past, hump-nosed vipers (Hypnalespecies) were considered moderately venomous snakes whose bites result mainly in local envenoming. However, a variety of severe local effects, hemostatic dysfunction, microangiopathic hemolysis, kidney injury and death have been reported following envenoming byHypnalespecies. We systematically reviewed the medical literature on the epidemiology, toxin profile, diagnosis, and clinical, laboratory and postmortem features of hump-nosed viper envenoming, and highlight the need for development of an effective antivenom.

Hypnale; Hump-nosed viper; Envenoming; Viper; Venom; Antivenom


Introduction

Hump-nosed viper (Hypnale) bite is an important yet under-recognized cause of morbidity and mortality in Southern India and Sri Lanka, where three species have been identified, namelyHypnale hypnale, H. zaraandH. nepa. Specifically,H. hypnalehas been reported from Sri Lanka and the Western Ghats of South India, while the other two species are endemic to Sri Lanka alone[1 Maduwage K, Silva A, Manamendra-Arachchi K, Pethiyagoda R: A taxonomic revision of the South Asian hump-nosed pit vipers (Squamata: Viperidae: Hypnale). Zootaxa 2009, 2232:1-28.]. In Sri Lanka, this small pit viper is known as ‘polon-thelissa’ (viper with an upturned lip) or ‘kunakatuwa’ (referring to the necrotic effects at the bite site) in Sinhala, and ‘kopi viriyan’ (coffee snake) in Tamil. In Kerala, India, it is called ‘churrutta’ in the Malayalam language.

Although formerly thought to result only in minor or local envenoming, hump-nosed viper (HNV) bite is now known to cause serious systemic toxicity and fatalities [2 Maduwage K, Isbister GK, Silva A, Bowatta S, Mendis S, Gawarammana I: Epidemiology and clinical effects of hump-nosed pit viper (Genus: Hypnale) envenoming in Sri Lanka. Toxicon2013, 61:11-15.

Simpson ID, Norris RL: Snakes of medical importance in India: is the concept of the "Big 4" still relevant and useful? Wilderness Environ Med 2007, 18(1):2-9.

Ariaratnam CA, Thuraisingam V, Kularatne SA, Sheriff MH, Theakston RD, De Silva A, Warrell DA: Frequent and potentially fatal envenoming by hump-nosed pit vipers (Hypnale hypnale and H. nepa) in Sri Lanka: lack of effective antivenom. Trans R Soc Trop Med Hyg 2008, 102(11):1120-1126.

Joseph JK, Simpson ID, Menon NC, Jose MP, Kulkarni KJ, Raghavendra GB, Warrell DA:First authenticated cases of life-threatening envenoming by the hump-nosed pit viper (Hypnale hypnale) in India. Trans R Soc Trop Med Hyg 2007, 101(1):85-90.
-6 Herath N, Wazil A, Kularatne S, Ratnatunga N, Weerakoon K, Badurdeen S, Rajakrishna P, Nanayakkara N, Dharmagunawardane D: Thrombotic microangiopathy and acute kidney injury in hump-nosed viper (Hypnale species) envenoming: a descriptive study in Sri Lanka. Toxicon 2012, 60(1):61-65.]. Clinical manifestations of systemic envenoming by this snake include acute kidney injury, hematological manifestations, and other organ involvement, in some cases leading to death. Several unusual manifestations have also been reported. HNV is now recognized as a highly venomous snake, alongside the Indian cobra (Naja naja), the common krait (Bungarus caeruleus), Russell's viper (Daboia russelii) and the saw-scaled viper (Echis carinatus) [3 Simpson ID, Norris RL: Snakes of medical importance in India: is the concept of the "Big 4" still relevant and useful? Wilderness Environ Med 2007, 18(1):2-9.]. It is the commonest cause of snakebite envenoming in Sri Lanka [7 Kasturiratne A, Pathmeswaran A, Fonseka MM, Lalloo DG, Brooker S, De Silva HJ:Estimates of disease burden due to land-snake bite in Sri Lankan hospitals. Southeast Asian J Trop Med Public Health 2005, 36(3):733-740.,8 De Silva A, Ranasinghe L: Epidemiology of snake-bite in Sri Lanka: a review. Ceylon Med J 1983, 28(3):144-154.]. The clinical and epidemiological importance of HNV bite is under-recognized, and currently no effective antivenom exists. In this paper we review the published literature on the epidemiology, clinical manifestations, and treatment of envenoming following HNV bite.

We performed a systematic review of the published literature. The databases Medline, Embase and Scopus were searched using the terms ‘hypnale’ OR ‘hump nosed’ OR ‘hump-nosed viper’ in any field, with no date limits. The search was performed on March 22, 2014. A combined search of Medline and Embase resulted in 50 hits; Scopus produced 62 hits. Databases were merged and duplicates removed. The abstracts were read through by two authors independently (MCS and SR), and relevant papers identified. Related references were also included. Data was extracted by two authors (MCS and SR), and crosschecked by the other two authors (MRN and MJY). Where conflicting data were present, a consensus was arrived upon by discussion between all the authors. The inter-rater agreement was 100%. The full text was obtained in 45 papers. A total of 40 papers provided useful data.

Review

Epidemiology

HNV accounts for between 27 and 77% of venomous snakebites in Sri Lanka and south India[4 Ariaratnam CA, Thuraisingam V, Kularatne SA, Sheriff MH, Theakston RD, De Silva A, Warrell DA: Frequent and potentially fatal envenoming by hump-nosed pit vipers (Hypnale hypnale and H. nepa) in Sri Lanka: lack of effective antivenom. Trans R Soc Trop Med Hyg 2008, 102(11):1120-1126.,5 Joseph JK, Simpson ID, Menon NC, Jose MP, Kulkarni KJ, Raghavendra GB, Warrell DA:First authenticated cases of life-threatening envenoming by the hump-nosed pit viper (Hypnale hypnale) in India. Trans R Soc Trop Med Hyg 2007, 101(1):85-90.,8 De Silva A, Ranasinghe L: Epidemiology of snake-bite in Sri Lanka: a review. Ceylon Med J 1983, 28(3):144-154.,9 Seneviratne SL, Opanayaka CJ, Ratnayake NS, Kumara KE, Sugathadasa AM, Weerasuriya N, Wickrama WA, Gunatilake SB, De Silva HJ: Use of antivenom serum in snake bite: a prospective study of hospital practice in the Gampaha district. Ceylon Med J 2000, 45(2):65-68.]. In southwestern India (Kerala), in the year 2007,H. hypnalewas identified as a common and dangerous source of envenoming, second only to Russell's viper. Deaths have been subsequently recorded in India following HNV envenoming [5 Joseph JK, Simpson ID, Menon NC, Jose MP, Kulkarni KJ, Raghavendra GB, Warrell DA:First authenticated cases of life-threatening envenoming by the hump-nosed pit viper (Hypnale hypnale) in India. Trans R Soc Trop Med Hyg 2007, 101(1):85-90.,1010  Kumar V, Sabitha P: Inadequacy of present polyspecific anti snakevenom – a study from central Kerala. Indian J Pediatr2011, 78(10):1225-1228.]. In a prospective multicenter study involving ten hospitals in Sri Lanka, 302 HNV bite victims were identified out of 860 patients with bites by identified snakes (35%). These were mostly men between the ages 11 and 51 years, bitten commonly at night on their feet or ankles near their homes [4 Ariaratnam CA, Thuraisingam V, Kularatne SA, Sheriff MH, Theakston RD, De Silva A, Warrell DA: Frequent and potentially fatal envenoming by hump-nosed pit vipers (Hypnale hypnale and H. nepa) in Sri Lanka: lack of effective antivenom. Trans R Soc Trop Med Hyg 2008, 102(11):1120-1126.]. The case fatality rate resulting from HNV bite was 1.7%, all due to acute kidney injury. Similar findings had been reported previously in a single-center prospective study in Avissawella, Sri Lanka, although fatalities were not seen [1111  Sellahewa KH, Kumararatne MP: Envenomation by the hump-nosed viper (Hypnale hypnale). Am J Trop Med Hyg 1994, 51(6):823-825.].

HNV was the commonest amongst cases of identified snakebite, in a three-year hospital based observational study from 2006 in the central hills of Sri Lanka [1212  Kularatne K, Budagoda S, Maduwage K, Naser K, Kumarasiri R, Kularatne S: Parallels between Russell's viper (Daboia russelii) and hump-nosed viper (Hypnalespecies) bites in the central hills of Sri Lanka amidst the heavy burden of unidentified snake bites. Asian Pac J Trop Med 2011, 4(7):564-567.]. Notably, the majority (61%) of victims had been bitten in a home garden. However, in this study there were large numbers of unidentified snakebites that did not result in envenoming. Another recent prospective hospital-based clinical study in Sri Lanka of proven HNV bites identified 114 definite cases [2 Maduwage K, Isbister GK, Silva A, Bowatta S, Mendis S, Gawarammana I: Epidemiology and clinical effects of hump-nosed pit viper (Genus: Hypnale) envenoming in Sri Lanka. Toxicon2013, 61:11-15.]. Most bites were on the lower limbs and during the daytime.H. hypnalebites were usually in home gardens, whilstH. zaraandH. nepabites occurred in the forests and tea estates respectively. In a large case series spanning 1990–2008, of 1543 patients with HNV bite, 4.34% were found to have developed systemic envenoming; only two patients died [1313  Wijewantha HS, Sellahewa KH: Hump nosed viper bite in Sri Lanka-descriptive observational study of 1543 cases. Asian Pac J Trop Med 2010, 3(11):902-905.]. The pattern of bites among children may differ slightly from that of the adult population. One study in the pediatric population showed that bites in children occur most commonly on the feet, and then the hands, mostly following provocation, and take place between 5 and 10 pm [1414  Karunathilaka DH, Herath GWDS, Lalani HHS, Perera KDNI: Envenomation by the hump nosed viper (hypnale hypnale) in children: a pilot study. Sri Lanka J Child Health 2001, 30(1):8-11.]. Overall, systemic envenoming is seen in a significant proportion of patients with HNV bite, although mortality appears to be low. Most reported cases of systemic envenoming are withH. hypnale[2 Maduwage K, Isbister GK, Silva A, Bowatta S, Mendis S, Gawarammana I: Epidemiology and clinical effects of hump-nosed pit viper (Genus: Hypnale) envenoming in Sri Lanka. Toxicon2013, 61:11-15.]. A single case report describes coagulopathy and acute kidney injury leading to death after confirmedH. zaraenvenoming [1515  Maduwage K, Kularatne K, Wazil A, Gawarammana I: Coagulopthy, acute kidney injury and death following Hypnale zara envenoming: the first case report from Sri Lanka. Toxicon 2011, 58(8):641-643.]. There are no reported cases of systemic envenoming or fatality due to aH. nepabite.

Toxin profile

In vitrostudies have found that the threeHypnalevenoms in Sri Lanka display similar chromatographic profiles [1616  Maduwage K, Hodgson WC, Konstantakopoulos N, O'Leary MA, Gawarammana I, Isbister GK: The in vitro toxicity of venoms from South Asian hump-nosed pit vipers (Viperidae: Hypnale). J Venom Res 2011, 2:17-23.]. Potent cytotoxicity, weak neurotoxic and myotoxic activity, mild procoagulant activity and also phospholipase activity are present in HNV venom. These activities are not neutralized by the locally available polyvalent antivenom. High activity levels of thrombin-like enzyme, proteases, phospholipase A2, L-amino acid oxidase and hyaluronidase may explain the hematological manifestations described below. The thrombin-like enzyme, which is highly acidic, is likely to exist in multiple isoforms (as evidenced by its chromatographic patterns). The hemorrhagic and necrotic activities of the venom are probably associated with the proteolytic enzyme found mainly in the basic fraction [1717  Tan CH, Sim SM, Gnanathasan CA, Fung SY, Ponnudurai G, Pailoor J, Tan NH: Enzymatic and toxinological activities of Hypnale hypnale (hump-nosed pit viper) venom and its fractionation by ion exchange high performance liquid chromatography. J Venom Anim Toxins incl Trop Dis 2011, 17(4):473-485. [http://dx.doi.org/10.1590/S1678-91992011000400015 webcite]].In vivostudies in mice also suggest thatH. hypnalevenom is more toxic compared to the other two species, with histopathological changes as well as lethality occurring with lower doses of venom [1818  Silva A, Gunawardena P, Weilgama D, Maduwage K, Gawarammana I: Comparative in-vivo toxicity of venoms from South Asian hump-nosed pit vipers (Viperidae: Crotalinae: Hypnale).BMC Res Notes 2012, 5:471.].

Diagnosis

Identification of the snake by medical personnel (or sometimes a herpetologist) viewing the dead snake or a photograph is the commonest means of diagnosingHypnalesnakebite [2 Maduwage K, Isbister GK, Silva A, Bowatta S, Mendis S, Gawarammana I: Epidemiology and clinical effects of hump-nosed pit viper (Genus: Hypnale) envenoming in Sri Lanka. Toxicon2013, 61:11-15.,9 Seneviratne SL, Opanayaka CJ, Ratnayake NS, Kumara KE, Sugathadasa AM, Weerasuriya N, Wickrama WA, Gunatilake SB, De Silva HJ: Use of antivenom serum in snake bite: a prospective study of hospital practice in the Gampaha district. Ceylon Med J 2000, 45(2):65-68.,1313  Wijewantha HS, Sellahewa KH: Hump nosed viper bite in Sri Lanka-descriptive observational study of 1543 cases. Asian Pac J Trop Med 2010, 3(11):902-905.]. However, misidentification rates as high as 6% by hospital staff have been reported [1919  Ariaratnam CA, Sheriff MH, Arambepola C, Theakston RD, Warrell DA: Syndromic approach to treatment of snake bite in Sri Lanka based on results of a prospective national hospital-based survey of patients envenomed by identified snakes. Am J Trop Med Hyg 2009, 81(4):725-731.]. Misidentification commonly occurs between Russell’s viper and the saw-scaled viper, which may contribute to confusion regarding clinical manifestations of severity [5 Joseph JK, Simpson ID, Menon NC, Jose MP, Kulkarni KJ, Raghavendra GB, Warrell DA:First authenticated cases of life-threatening envenoming by the hump-nosed pit viper (Hypnale hypnale) in India. Trans R Soc Trop Med Hyg 2007, 101(1):85-90.,1919  Ariaratnam CA, Sheriff MH, Arambepola C, Theakston RD, Warrell DA: Syndromic approach to treatment of snake bite in Sri Lanka based on results of a prospective national hospital-based survey of patients envenomed by identified snakes. Am J Trop Med Hyg 2009, 81(4):725-731.]. Where the snake is unidentified, syndromic diagnosis is a very useful tool; this is frequently used in clinical settings[1919  Ariaratnam CA, Sheriff MH, Arambepola C, Theakston RD, Warrell DA: Syndromic approach to treatment of snake bite in Sri Lanka based on results of a prospective national hospital-based survey of patients envenomed by identified snakes. Am J Trop Med Hyg 2009, 81(4):725-731.]. The basis of syndromic diagnosis is that, where the snake has not been identified visually, it is possible to make an identification based on the clinical syndrome it produces, using a validated algorithm. Its specificity for Russell’s viper and HNV is high, albeit with poor sensitivity. The key clinical features in this tool favoring HNV bite are local envenoming, incoagulable blood, and renal failure; however, these are also provoked by Russell’s viper [1919  Ariaratnam CA, Sheriff MH, Arambepola C, Theakston RD, Warrell DA: Syndromic approach to treatment of snake bite in Sri Lanka based on results of a prospective national hospital-based survey of patients envenomed by identified snakes. Am J Trop Med Hyg 2009, 81(4):725-731.].

Alternate scoring systems have been suggested but are insensitive in diagnosing HNV and saw scaled viper envenoming, although they help differentiate HNV bite from Russell's viper, krait and cobra bites [2020  Pathmeswaran A, Kasturiratne A, Fonseka M, Nandasena S, Lalloo DG, De Silva HJ:Identifying the biting species in snakebite by clinical features: an epidemiological tool for community surveys. Trans R Soc Trop Med Hyg 2006, 100(9):874-878.]. Immune assays based on the antigenic profile of viper toxins that may differentiate between species of vipers have been tested. These have the potential to become valuable tools in diagnosing and differentiating HNV bite from other snakebites [2121  Tan CH, Tan NH, Sim SM, Fung SY, Gnanathasan CA: Immunological properties ofHypnale hypnale (hump-nosed pit viper) venom: antibody production with diagnostic and therapeutic potentials. Acta Trop 2012, 122(3):267-275.]. Cross-reactivity studies using indirect ELISA have shown that anti-Hypnale hypnaleIgG cross-reacts extensively with several Asiatic crotalid venoms. Further studies have shown that this assay is able to distinguish and quantify venoms ofH. hypnale, Daboia russeliiandEchis carinatus sinhaleyus.

Envenoming

Local effects

Pain and fang marks are invariably found after HNV bite. Local envenoming is the commonest manifestation, with an incidence of approximately 90% [2 Maduwage K, Isbister GK, Silva A, Bowatta S, Mendis S, Gawarammana I: Epidemiology and clinical effects of hump-nosed pit viper (Genus: Hypnale) envenoming in Sri Lanka. Toxicon2013, 61:11-15.,4 Ariaratnam CA, Thuraisingam V, Kularatne SA, Sheriff MH, Theakston RD, De Silva A, Warrell DA: Frequent and potentially fatal envenoming by hump-nosed pit vipers (Hypnale hypnale and H. nepa) in Sri Lanka: lack of effective antivenom. Trans R Soc Trop Med Hyg 2008, 102(11):1120-1126.]. This can be severe, and lead to tissue necrosis. Local pain, swelling, induration, local hemorrhagic blister formation, local bleeding, local necrosis, need for amputation and skin grafting, and regional lymphadenopathy have all been reported [2 Maduwage K, Isbister GK, Silva A, Bowatta S, Mendis S, Gawarammana I: Epidemiology and clinical effects of hump-nosed pit viper (Genus: Hypnale) envenoming in Sri Lanka. Toxicon2013, 61:11-15.,4 Ariaratnam CA, Thuraisingam V, Kularatne SA, Sheriff MH, Theakston RD, De Silva A, Warrell DA: Frequent and potentially fatal envenoming by hump-nosed pit vipers (Hypnale hypnale and H. nepa) in Sri Lanka: lack of effective antivenom. Trans R Soc Trop Med Hyg 2008, 102(11):1120-1126.,1111  Sellahewa KH, Kumararatne MP: Envenomation by the hump-nosed viper (Hypnale hypnale). Am J Trop Med Hyg 1994, 51(6):823-825.,2222  Ramachandran S, Ganaikabahu B, Pushparajan K, Wijesekera J:Electroencephalographic abnormalities in patients with snake bites. Am J Trop Med Hyg 1995, 52(1):25-28.]. However, severe local envenoming with proximal spread is relatively less common, and was seen in only 16 of 114 study subjects in a recent hospital-based study [2 Maduwage K, Isbister GK, Silva A, Bowatta S, Mendis S, Gawarammana I: Epidemiology and clinical effects of hump-nosed pit viper (Genus: Hypnale) envenoming in Sri Lanka. Toxicon2013, 61:11-15.].

Systemic envenoming

Although HNV bite was previously thought only to result in local envenoming, systemic effects are now a recognized phenomenon, with more than one organ system being affected [2 Maduwage K, Isbister GK, Silva A, Bowatta S, Mendis S, Gawarammana I: Epidemiology and clinical effects of hump-nosed pit viper (Genus: Hypnale) envenoming in Sri Lanka. Toxicon2013, 61:11-15.,4 Ariaratnam CA, Thuraisingam V, Kularatne SA, Sheriff MH, Theakston RD, De Silva A, Warrell DA: Frequent and potentially fatal envenoming by hump-nosed pit vipers (Hypnale hypnale and H. nepa) in Sri Lanka: lack of effective antivenom. Trans R Soc Trop Med Hyg 2008, 102(11):1120-1126.,1111  Sellahewa KH, Kumararatne MP: Envenomation by the hump-nosed viper (Hypnale hypnale). Am J Trop Med Hyg 1994, 51(6):823-825.,1313  Wijewantha HS, Sellahewa KH: Hump nosed viper bite in Sri Lanka-descriptive observational study of 1543 cases. Asian Pac J Trop Med 2010, 3(11):902-905.]. The variable frequency and severity of systemic envenoming could at least partly be explained by variations in toxicity between the differentHypnalespecies [2 Maduwage K, Isbister GK, Silva A, Bowatta S, Mendis S, Gawarammana I: Epidemiology and clinical effects of hump-nosed pit viper (Genus: Hypnale) envenoming in Sri Lanka. Toxicon2013, 61:11-15.]. HNV bites appear to result in a higher incidence of both local and systemic effects in children, especially those under three years; systemic effects appear to occur early on, and show an inverse relationship to body surface area[1414  Karunathilaka DH, Herath GWDS, Lalani HHS, Perera KDNI: Envenomation by the hump nosed viper (hypnale hypnale) in children: a pilot study. Sri Lanka J Child Health 2001, 30(1):8-11.].

Vascular and hematological manifestations

Individual reports of coagulopathy following hump-nosed viper envenoming were reported in the 1990s [2323  De Silva A, Wijekoon AS, Jayasena L, Abeysekera CK, Bao CX, Hutton RA, Warrell DA:Haemostatic dysfunction and acute renal failure following envenoming by Merrem's hump-nosed viper (Hypnale hypnale) in Sri Lanka: first authenticated case. Trans R Soc Trop Med Hyg1994, 88(2):209-212.

24  Premawardena AP, Seneviratne SL, Gunatilake SB, De Silva HJ: Excessive fibrinolysis: the coagulopathy following Merrem's hump-nosed viper (Hypnale hypnale) bites. Am J Trop Med Hyg1998, 58(6):821-823.
-2525  Premawardena AP, Seneviratne SL, Jayanthi S, Gunatilake SB, De Silva HJ: Coagulopathy and fibrinolysis following the bite of a hump-nosed viper (Hypnale hypnale).Trans R Soc Trop Med Hyg1996, 90:293.]. In a prospective study of 56 patients with proven HNV bites, 12 patients (21.4%) developed continued oozing of blood from the site of the bite, with prolonged clotting time [2424  Premawardena AP, Seneviratne SL, Gunatilake SB, De Silva HJ: Excessive fibrinolysis: the coagulopathy following Merrem's hump-nosed viper (Hypnale hypnale) bites. Am J Trop Med Hyg1998, 58(6):821-823.]. Low fibrinogen levels and increased fibrinogen degradation products in plasma were also demonstrated in these patients. Bleeding time, platelet count, prothrombin time, and partial thromboplastin time with kaolin were normal. The authors suggested the use of whole-blood clotting time to monitor cases of hump-nosed viper bite; this is standard practice in hospitals in Sri Lanka now. In a recent paper on syndromic diagnosis of snakebite, the authors suggested that coagulopathy was present in 39% of 302 patients with HNV bite, making it the second commonest manifestation after local envenoming [1919  Ariaratnam CA, Sheriff MH, Arambepola C, Theakston RD, Warrell DA: Syndromic approach to treatment of snake bite in Sri Lanka based on results of a prospective national hospital-based survey of patients envenomed by identified snakes. Am J Trop Med Hyg 2009, 81(4):725-731.]. Even where the whole-blood clotting time is normal, mild coagulopathy, evidenced by slight elevation of INR, low fibrinogen and factors V and VIII have been associated with HNV bite [2626  Maduwage K, Scorgie FE, Silva A, Shahmy S, Mohamed F, Abeysinghe C, Karunathilake H, Lincz LF, Gnanathasan CA, Isbister GK: Hump-nosed pit viper (Hypnale hypnale) envenoming causes mild coagulopathy with incomplete clotting factor consumption. Clin Toxicol (Phila)2013, 51(7):527-531.]. It is postulated that these abnormalities occur due to a thrombin-like enzyme contained in the venom; the clinical significance of these abnormalities is unclear.

Microangiopathic hemolytic anemia with thrombocytopenia, coagulopathy, fibrinolysis, thrombocytopenia or spontaneous systemic hemorrhage, and a case of hemolytic uremic syndrome, have been reported with HNV bite [5 Joseph JK, Simpson ID, Menon NC, Jose MP, Kulkarni KJ, Raghavendra GB, Warrell DA:First authenticated cases of life-threatening envenoming by the hump-nosed pit viper (Hypnale hypnale) in India. Trans R Soc Trop Med Hyg 2007, 101(1):85-90.,6 Herath N, Wazil A, Kularatne S, Ratnatunga N, Weerakoon K, Badurdeen S, Rajakrishna P, Nanayakkara N, Dharmagunawardane D: Thrombotic microangiopathy and acute kidney injury in hump-nosed viper (Hypnale species) envenoming: a descriptive study in Sri Lanka. Toxicon 2012, 60(1):61-65.,2626  Maduwage K, Scorgie FE, Silva A, Shahmy S, Mohamed F, Abeysinghe C, Karunathilake H, Lincz LF, Gnanathasan CA, Isbister GK: Hump-nosed pit viper (Hypnale hypnale) envenoming causes mild coagulopathy with incomplete clotting factor consumption. Clin Toxicol (Phila)2013, 51(7):527-531.

27  Karunatilake H, Nayakarathna T, Atapattu S, Saparamadu T, Dharmasena S: Thrombotic microangiopathy and fibrinolysis after hump-nosed viper envenomation. Ceylon Med J 2012, 57(1):45-46.
-2828  Mitrakrishnan JY, Bandula CW, Mitrakrishnan CS, Somaratna K, Jeyalakshmy S:Haemolytic uremic syndrome a hitherto unreported complication of humpnosed viper envenomation. Indian J Hematol Blood Transfus2013, 29(2):116-118.]. Consumptive coagulopathy has been purported to be the mechanism for these manifestations in some cases [2727  Karunatilake H, Nayakarathna T, Atapattu S, Saparamadu T, Dharmasena S: Thrombotic microangiopathy and fibrinolysis after hump-nosed viper envenomation. Ceylon Med J 2012, 57(1):45-46.,2828  Mitrakrishnan JY, Bandula CW, Mitrakrishnan CS, Somaratna K, Jeyalakshmy S:Haemolytic uremic syndrome a hitherto unreported complication of humpnosed viper envenomation. Indian J Hematol Blood Transfus2013, 29(2):116-118.]. Isbister [2929  Isbister GK: Snakebite doesn't cause disseminated intravascular coagulation: coagulopathy and thrombotic microangiopathy in snake envenoming. Semin Thromb Hemost 2010, 36(4):444-451.] described this venom-induced coagulopathy as constituting the commonest coagulopathy associated with snake envenoming. This has been likened to disseminated intravascular coagulation (DIC), because of certain similarities seen between the two conditions, e.g., elevated D-dimer, prolonged prothrombin time, and low fibrinogen; however, important differences between venom-induced coagulopathy and DIC have been demonstrated [2929  Isbister GK: Snakebite doesn't cause disseminated intravascular coagulation: coagulopathy and thrombotic microangiopathy in snake envenoming. Semin Thromb Hemost 2010, 36(4):444-451.]. The onset and resolution were rapid, while there was no evidence of either systemic microthrombi or end-organ failure. In a portion of patients with venom-induced coagulopathy, however, a clinical syndrome consistent with thrombotic microangiopathy has been reported, characterized by thrombocytopenia, microangiopathic hemolytic anemia and acute kidney injury. This venom induced coagulopathy-related thrombotic microangiopathy appears to occur with several different snakebites worldwide, including vipers and elapids.

Renal toxicity

In mouse model studies, histopathogical examination of the kidneys have revealed proximal tubular cell injury and acute tubular necrosis with intact basement membrane, indicating possible direct nephrotoxicity following HNV envenoming [1818  Silva A, Gunawardena P, Weilgama D, Maduwage K, Gawarammana I: Comparative in-vivo toxicity of venoms from South Asian hump-nosed pit vipers (Viperidae: Crotalinae: Hypnale).BMC Res Notes 2012, 5:471.]. Renal toxicity was observed in around 19% of cases with HNV bite in a recent study, while death following acute kidney injury is well documented [4 Ariaratnam CA, Thuraisingam V, Kularatne SA, Sheriff MH, Theakston RD, De Silva A, Warrell DA: Frequent and potentially fatal envenoming by hump-nosed pit vipers (Hypnale hypnale and H. nepa) in Sri Lanka: lack of effective antivenom. Trans R Soc Trop Med Hyg 2008, 102(11):1120-1126.,6 Herath N, Wazil A, Kularatne S, Ratnatunga N, Weerakoon K, Badurdeen S, Rajakrishna P, Nanayakkara N, Dharmagunawardane D: Thrombotic microangiopathy and acute kidney injury in hump-nosed viper (Hypnale species) envenoming: a descriptive study in Sri Lanka. Toxicon 2012, 60(1):61-65.,3030  Varagunam T, Panabokke RG: Bilateral cortical necrosis of the kidneys following snakebite. Postgrad Med J 1970, 46(537):449-451.,3131  Sawai Y, Toriba M, Itokawa H, De Silva A, Perera GL, Kottegoda MB: Death from snake-bite in Anuradhapura District. Ceylon Med J1983, 28(3):163-169.]. Renal toxicity is characterized by features of acute kidney injury, i.e., oliguria, dark urine, fluid retention, uremia and elevated serum creatinine, often requiring dialysis[4 Ariaratnam CA, Thuraisingam V, Kularatne SA, Sheriff MH, Theakston RD, De Silva A, Warrell DA: Frequent and potentially fatal envenoming by hump-nosed pit vipers (Hypnale hypnale and H. nepa) in Sri Lanka: lack of effective antivenom. Trans R Soc Trop Med Hyg 2008, 102(11):1120-1126.

Joseph JK, Simpson ID, Menon NC, Jose MP, Kulkarni KJ, Raghavendra GB, Warrell DA:First authenticated cases of life-threatening envenoming by the hump-nosed pit viper (Hypnale hypnale) in India. Trans R Soc Trop Med Hyg 2007, 101(1):85-90.
-6 Herath N, Wazil A, Kularatne S, Ratnatunga N, Weerakoon K, Badurdeen S, Rajakrishna P, Nanayakkara N, Dharmagunawardane D: Thrombotic microangiopathy and acute kidney injury in hump-nosed viper (Hypnale species) envenoming: a descriptive study in Sri Lanka. Toxicon 2012, 60(1):61-65.,1414  Karunathilaka DH, Herath GWDS, Lalani HHS, Perera KDNI: Envenomation by the hump nosed viper (hypnale hypnale) in children: a pilot study. Sri Lanka J Child Health 2001, 30(1):8-11.,1515  Maduwage K, Kularatne K, Wazil A, Gawarammana I: Coagulopthy, acute kidney injury and death following Hypnale zara envenoming: the first case report from Sri Lanka. Toxicon 2011, 58(8):641-643.,2323  De Silva A, Wijekoon AS, Jayasena L, Abeysekera CK, Bao CX, Hutton RA, Warrell DA:Haemostatic dysfunction and acute renal failure following envenoming by Merrem's hump-nosed viper (Hypnale hypnale) in Sri Lanka: first authenticated case. Trans R Soc Trop Med Hyg1994, 88(2):209-212.,2727  Karunatilake H, Nayakarathna T, Atapattu S, Saparamadu T, Dharmasena S: Thrombotic microangiopathy and fibrinolysis after hump-nosed viper envenomation. Ceylon Med J 2012, 57(1):45-46.,2828  Mitrakrishnan JY, Bandula CW, Mitrakrishnan CS, Somaratna K, Jeyalakshmy S:Haemolytic uremic syndrome a hitherto unreported complication of humpnosed viper envenomation. Indian J Hematol Blood Transfus2013, 29(2):116-118.,3030  Varagunam T, Panabokke RG: Bilateral cortical necrosis of the kidneys following snakebite. Postgrad Med J 1970, 46(537):449-451.,3232  Jeevagan V, Chang T, Gnanathasan CA: Acute ischemic stroke following Hump-nosed viper envenoming; first authenticated case. Thromb J 2012, 10:21. doi:10.1186/1477-9560-10-21]. Both enzymatic activity in venom and immunologic mechanisms have been implicated in causing renal damage following snakebite, with the latter playing only a minor role. Hemodynamic alterations caused by vasoactive mediators and cytokines also contribute to renal damage [3333  Kanjanabuch T, Sitprija V: Snakebite nephrotoxicity in Asia. Semin Nephrol 2008, 28(4):363-372.]. Bilateral cortical necrosis, characterized by irregular areas of coagulative necrosis involving both glomeruli and tubules in the cortices, have been demonstrated in postmortem studies as far back as in 1970 [3030  Varagunam T, Panabokke RG: Bilateral cortical necrosis of the kidneys following snakebite. Postgrad Med J 1970, 46(537):449-451.]. Similar postmortem findings have been described in a case ofH. zaraenvenoming complicated by coagulopathy [1515  Maduwage K, Kularatne K, Wazil A, Gawarammana I: Coagulopthy, acute kidney injury and death following Hypnale zara envenoming: the first case report from Sri Lanka. Toxicon 2011, 58(8):641-643.].

In a prospective observational study carried out at the Nephrology Unit, Kandy, Sri Lanka from October 2010 to October 2011, out of 11 patients with acute kidney injury following HNV bites, all required renal replacement therapy, seven developed thrombotic microangiopathy with evidence of microangiopathic hemolytic anemia (MAHA), thrombocytopenia and severe anemia necessitating multiple blood transfusions, and two progressed to chronic renal failure [6 Herath N, Wazil A, Kularatne S, Ratnatunga N, Weerakoon K, Badurdeen S, Rajakrishna P, Nanayakkara N, Dharmagunawardane D: Thrombotic microangiopathy and acute kidney injury in hump-nosed viper (Hypnale species) envenoming: a descriptive study in Sri Lanka. Toxicon 2012, 60(1):61-65.]. Autopsy in two fatalities demonstrated thrombotic microangiopathy. The authors queried a causal link between thrombosis and renal damage. Chronic kidney disease, whose occurrence is predicted by the duration of renal replacement therapy and failure to normalize renal function after one year, is also known to occur following HNV bite. Glomerulosclerosis is the predominant histological finding[3434  Herath HM, Wazil AW, Abeysekara DT, Jeewani ND, Weerakoon KG, Ratnatunga NV, Bandara EH, Kularatne SA: Chronic kidney disease in snake envenomed patients with acute kidney injury in Sri Lanka: a descriptive study. Postgrad Med J 2012, 88(1037):138-142.,3535  Herath HNMJ, Wazil AWM, Abeysekara DTDJ, Jeewani NDC, Weerakoon KGAD, Rathnathunga NVI, Bandara EHCK, Kularathne SAM: Snake bite causing chronic kidney diseases analysis of 42 cases in the nephrology unit, Kandy, Sri Lanka. InProceedings of the 12th Asian Pacific Congress of Nephrology.Nephrology 2010., 15(Suppl 3)].

Neurological effects

Direct neurological toxicity or effects on the neuromuscular junction have not been described in relation to HNV envenoming. EEG abnormalities without clinical neurological derangement have been observed in humans following HNV envenoming [2222  Ramachandran S, Ganaikabahu B, Pushparajan K, Wijesekera J:Electroencephalographic abnormalities in patients with snake bites. Am J Trop Med Hyg 1995, 52(1):25-28.]. There is a single case report of an ischemic stroke following HNV bite. In this instance, the platelets were normal, and there was no evidence of coagulopathy, although acute kidney injury that had been present was resolved. It was suggested that the pathophysiology was of a vaso-occlusive nature [3232  Jeevagan V, Chang T, Gnanathasan CA: Acute ischemic stroke following Hump-nosed viper envenoming; first authenticated case. Thromb J 2012, 10:21. doi:10.1186/1477-9560-10-21].

Effects on the heart

Transient ECG changes and symptoms suggestive of cardiac involvement have been observed with HNV envenoming. Electrolyte imbalance and hemodynamic instability could contribute towards these. However, no evidence of myocardial damage, characterized by elevated cardiac troponin, has been demonstrated with HNV envenoming [3636  Seneviratne SL, Gunatilake SB, Fonseka MM, Adhikari AA, De Silva HJ: Lack of myocardial damage following Sri Lankan Russell's viper and hump-nosed viper bites. Ceylon Med J 1999, 44(2):70-73.].

Pulmonary effects

Pulmonary edema has been documented in humans following envenoming byHypnale hypnaleorHypnale zara[5 Joseph JK, Simpson ID, Menon NC, Jose MP, Kulkarni KJ, Raghavendra GB, Warrell DA:First authenticated cases of life-threatening envenoming by the hump-nosed pit viper (Hypnale hypnale) in India. Trans R Soc Trop Med Hyg 2007, 101(1):85-90.,1515  Maduwage K, Kularatne K, Wazil A, Gawarammana I: Coagulopthy, acute kidney injury and death following Hypnale zara envenoming: the first case report from Sri Lanka. Toxicon 2011, 58(8):641-643.]. However, there is no conclusive evidence to suggest that lung injury occurs as a specific effect of HNV envenoming. Studies in mice have shown that HNV venom can induce pulmonary hemorrhage [1818  Silva A, Gunawardena P, Weilgama D, Maduwage K, Gawarammana I: Comparative in-vivo toxicity of venoms from South Asian hump-nosed pit vipers (Viperidae: Crotalinae: Hypnale).BMC Res Notes 2012, 5:471.].

Gastrointestinal and liver effects

Nausea, vomiting, hematemesis (probably secondary to coagulopathy) and abdominal pain have been reported [4 Ariaratnam CA, Thuraisingam V, Kularatne SA, Sheriff MH, Theakston RD, De Silva A, Warrell DA: Frequent and potentially fatal envenoming by hump-nosed pit vipers (Hypnale hypnale and H. nepa) in Sri Lanka: lack of effective antivenom. Trans R Soc Trop Med Hyg 2008, 102(11):1120-1126.]. However, hepatic dysfunction has not been described.

Treatment

Treatment is mainly symptomatic and supportive. Analgesics, splinting of the bitten limb, wound care, and surgical management including skin grafting constitute the common approach employed against local envenoming. In rare cases, amputation may be needed. Antibiotics are often used routinely, despite lack of benefit in snakebite, and tetanus toxoid is also administered [4 Ariaratnam CA, Thuraisingam V, Kularatne SA, Sheriff MH, Theakston RD, De Silva A, Warrell DA: Frequent and potentially fatal envenoming by hump-nosed pit vipers (Hypnale hypnale and H. nepa) in Sri Lanka: lack of effective antivenom. Trans R Soc Trop Med Hyg 2008, 102(11):1120-1126.,1414  Karunathilaka DH, Herath GWDS, Lalani HHS, Perera KDNI: Envenomation by the hump nosed viper (hypnale hypnale) in children: a pilot study. Sri Lanka J Child Health 2001, 30(1):8-11.,3737  Kularatne SA, Kumarasiri PV, Pushpakumara SK, Dissanayaka WP, Ariyasena H, Gawarammana IB, Senanayake N: Routine antibiotic therapy in the management of the local inflammatory swelling in venomous snakebites: results of a placebo-controlled study. Ceylon Med J 2005, 50(4):151-155.]. Features of systemic envenoming are treated with supportive care. Renal replacement therapy is the mainstay of management of acute renal impairment, and may become necessary if chronic kidney disease occurs consequently [6 Herath N, Wazil A, Kularatne S, Ratnatunga N, Weerakoon K, Badurdeen S, Rajakrishna P, Nanayakkara N, Dharmagunawardane D: Thrombotic microangiopathy and acute kidney injury in hump-nosed viper (Hypnale species) envenoming: a descriptive study in Sri Lanka. Toxicon 2012, 60(1):61-65.,3434  Herath HM, Wazil AW, Abeysekara DT, Jeewani ND, Weerakoon KG, Ratnatunga NV, Bandara EH, Kularatne SA: Chronic kidney disease in snake envenomed patients with acute kidney injury in Sri Lanka: a descriptive study. Postgrad Med J 2012, 88(1037):138-142.,3535  Herath HNMJ, Wazil AWM, Abeysekara DTDJ, Jeewani NDC, Weerakoon KGAD, Rathnathunga NVI, Bandara EHCK, Kularathne SAM: Snake bite causing chronic kidney diseases analysis of 42 cases in the nephrology unit, Kandy, Sri Lanka. InProceedings of the 12th Asian Pacific Congress of Nephrology.Nephrology 2010., 15(Suppl 3)]. Optimized administration of blood components, correction of coagulopathy, and plasma exchange may be required when hematologic derangements occur. No clear trial based evidence is available showing benefit of these interventions. There are no specific protocols for managing envenoming following HNV bite, and standard guidelines for snakebite management are followed [3838  Fernando M: Guidelines for the management of snakebite in hospital. Sri Lanka: Expert Committee on snakebite Sri Lanka Medical Association; 2013.].

Antivenom

No specific or polyvalent antivenom is available yet for human use in HNV envenoming [3939  Tan CH, Tan NH, Sim SM, Fung SY, Jayalakshmi P, Gnanathasan CA: Nephrotoxicity of hump-nosed pit viper (Hypnale hypnale) venom in mice is preventable by the paraspecific Hemato polyvalent antivenom (HPA). Toxicon 2012, 60(7):1259-1262.]. The currently used polyvalent antivenom is ineffective in the treatment of HNV envenomation, and is associated with a high incidence of reactions [4 Ariaratnam CA, Thuraisingam V, Kularatne SA, Sheriff MH, Theakston RD, De Silva A, Warrell DA: Frequent and potentially fatal envenoming by hump-nosed pit vipers (Hypnale hypnale and H. nepa) in Sri Lanka: lack of effective antivenom. Trans R Soc Trop Med Hyg 2008, 102(11):1120-1126.,9 Seneviratne SL, Opanayaka CJ, Ratnayake NS, Kumara KE, Sugathadasa AM, Weerasuriya N, Wickrama WA, Gunatilake SB, De Silva HJ: Use of antivenom serum in snake bite: a prospective study of hospital practice in the Gampaha district. Ceylon Med J 2000, 45(2):65-68.,4040  Sellahewa KH, Gunawardena G, Kumararatne MP: Efficacy of antivenom in the treatment of severe local envenomation by the hump-nosed viper (Hypnale hypnale). Am J Trop Med Hyg 1995, 53(3):260-262.].In vivoanimal studies evaluating potential alternative antivenom preparations for HNV show mixed results [2121  Tan CH, Tan NH, Sim SM, Fung SY, Gnanathasan CA: Immunological properties ofHypnale hypnale (hump-nosed pit viper) venom: antibody production with diagnostic and therapeutic potentials. Acta Trop 2012, 122(3):267-275.]. Trials in mice have found hematopolyvalent antivenom to be efficacious following experimental envenoming withH. hypnalevenom. This was shown to effectively prevent acute kidney injury and death [4141  Tan CH, Leong PK, Fung SY, Sim SM, Ponnudurai G, Ariaratnam C, Khomvilai S, Sitprija V, Tan NH: Cross neutralization of Hypnale hypnale (hump-nosed pit viper) venom by polyvalent and monovalent Malayan pit viper antivenoms in vitro and in a rodent model. Acta Trop 2011, 117(2):119-124.].In vitroneutralization studies showed that the hematopolyvalent antivenom effectively neutralized the lethality ofH. hypnalevenom, as well as the hemorrhagic, procoagulant, nephrotoxic, and necrotic activities of the venom [3939  Tan CH, Tan NH, Sim SM, Fung SY, Jayalakshmi P, Gnanathasan CA: Nephrotoxicity of hump-nosed pit viper (Hypnale hypnale) venom in mice is preventable by the paraspecific Hemato polyvalent antivenom (HPA). Toxicon 2012, 60(7):1259-1262.]. The monovalentCalloselasma rhodostomaantivenom also is also capable of neutralizing the lethality and toxic activities of the venom, but its potency was lower[4141  Tan CH, Leong PK, Fung SY, Sim SM, Ponnudurai G, Ariaratnam C, Khomvilai S, Sitprija V, Tan NH: Cross neutralization of Hypnale hypnale (hump-nosed pit viper) venom by polyvalent and monovalent Malayan pit viper antivenoms in vitro and in a rodent model. Acta Trop 2011, 117(2):119-124.].H. hypnalevenom elicited satisfactory titers of anti-Hypnale hypnaleIgG in rabbits after the third immunization. This anti-Hypnale hypnaleIgG, isolated using the caprylic acid precipitation method, was effective in neutralizing venom lethality (potency = 48 LD50per mL IgG) as well as its procoagulant, hemorrhagic and necrotic effects. This suggests the potential to produce a specific antivenom [2121  Tan CH, Tan NH, Sim SM, Fung SY, Gnanathasan CA: Immunological properties ofHypnale hypnale (hump-nosed pit viper) venom: antibody production with diagnostic and therapeutic potentials. Acta Trop 2012, 122(3):267-275.].

Outcome

Survival and minor effects is the norm after HNV bites, although fatalities are known to occur[2 Maduwage K, Isbister GK, Silva A, Bowatta S, Mendis S, Gawarammana I: Epidemiology and clinical effects of hump-nosed pit viper (Genus: Hypnale) envenoming in Sri Lanka. Toxicon2013, 61:11-15.,4 Ariaratnam CA, Thuraisingam V, Kularatne SA, Sheriff MH, Theakston RD, De Silva A, Warrell DA: Frequent and potentially fatal envenoming by hump-nosed pit vipers (Hypnale hypnale and H. nepa) in Sri Lanka: lack of effective antivenom. Trans R Soc Trop Med Hyg 2008, 102(11):1120-1126.,1111  Sellahewa KH, Kumararatne MP: Envenomation by the hump-nosed viper (Hypnale hypnale). Am J Trop Med Hyg 1994, 51(6):823-825.]. Chronic kidney disease is a recognized complication, as described above.

Conclusions

Formerly thought to result only in local envenoming, HNV bite can result in serious sequelae including death. Acute kidney injury and hematological manifestations are the predominant serious effects. Clinically significant neurotoxicity or cardiotoxicity does not occur. There are two key areas for future research: firstly, identification of clinical parameters and biochemical tests for early identification of systemic envenoming, i.e., early detection of coagulopathy and nephrotoxicity; secondly, the development of an efficacious specific antivenom for routine use.

References

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Publication Dates

  • Publication in this collection
    2014

History

  • Received
    13 Feb 2014
  • Reviewed
    30 May 2014
  • Accepted
    6 June 2014
Centro de Estudos de Venenos e Animais Peçonhentos (CEVAP/UNESP) Av. Universitária, 3780, Fazenda Lageado, Botucatu, SP, CEP 18610-034, Brasil, Tel.: +55 14 3880-7693 - Botucatu - SP - Brazil
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