Estimating economic and disease burden of snakebite in ASEAN countries using a decision analytic model.

BACKGROUND: Understanding the burden of snakebite is crucial for developing evidence-informed strategies to pursue the goal set by the World Health Organization to halve morbidity and mortality of snakebite by 2030. However, there was no such information in the Association of Southeast Asian Nations (ASEAN) countries. METHODOLOGY: A decision analytic model was developed to estimate annual burden of snakebite in seven countries, including Malaysia, Thailand, Indonesia, Philippines, Vietnam, Lao PDR, and Myanmar. Country-specific input parameters were sought from published literature, country's Ministry of Health, local data, and expert opinion. Economic burden was estimated from the societal perspective. Costs were expressed in 2019 US Dollars (USD). Disease burden was estimated as disability-adjusted life years (DALYs). Probabilistic sensitivity analysis was performed to estimate a 95% credible interval (CrI). PRINCIPAL FINDINGS: We estimated that annually there were 242,648 snakebite victims (95%CrI 209,810-291,023) of which 15,909 (95%CrI 7,592-33,949) were dead and 954 (95%CrI 383-1,797) were amputated. We estimated that 161,835 snakebite victims (69% of victims who were indicated for antivenom treatment) were not treated with antivenom. Annual disease burden of snakebite was estimated at 391,979 DALYs (95%CrI 187,261-836,559 DALYs) with total costs of 2.5 billion USD (95%CrI 1.2-5.4 billion USD) that were equivalent to 0.09% (95%CrI 0.04-0.20%) of the region's gross domestic product. >95% of the estimated burdens were attributed to premature deaths. CONCLUSION/SIGNIFICANCE: The estimated high burden of snakebite in ASEAN was demonstrated despite the availability of domestically produced antivenoms. Most burdens were attributed to premature deaths from snakebite envenoming which suggested that the remarkably high burden of snakebite could be averted. We emphasized the importance of funding research to perform a comprehensive data collection on epidemiological and economic burden of snakebite to eventually reveal the true burden of snakebite in ASEAN and inform development of strategies to tackle the problem of snakebite.

Situation of snakebite, antivenom market and access to antivenoms in ASEAN countries.

INTRODUCTION: Snakebite envenoming is a neglected tropical disease posing public health challenges globally. The Association of Southeast Asian Nations (ASEAN) countries are among the tropical regions with disproportionately high incidence of snakebite. Hence, this study aimed to review the situation of snakebite, antivenom market and access to antivenoms in ASEAN. METHODS: This mixed-methods study included comprehensive literature review and in-depth interviews with key informants to assess the situation of management system of snakebite, antivenom market and access to antivenoms in seven ASEAN countries, including Malaysia, Thailand, Indonesia, Philippines, Vietnam, Lao PDR and Myanmar. Data were analysed by a framework method. RESULTS: ASEAN have developed various strategies to improve outcomes of snakebite victims. Five domestic antivenom manufacturers in the region produce up to 288 375 vials of antivenoms annually with the value of US$13 058 053 million which could treat 42 213 snakebite victims. However, there remain challenges to be addressed especially the lack of snakebite-related informatics system, inadequate antivenoms at the healthcare facilities and when the majority of snakebite victims seek traditional healers instead of conventional treatment. CONCLUSION: Improving the situation of snakebite and antivenom is not only about the availability of antivenom, but the whole landscape of surrounding management and supporting system. The assessment of the situation of snakebite and antivenom is crucial for countries or regions where snakebites are prevalent to recognise their current standpoint to inform the development of strategies to achieve the goal set by the WHO of halving the global burden of snakebite by 2030.

Characteristics and significance of "green snake" bites in Myanmar, especially by the pit vipers Trimeresurus albolabris and Trimeresurus erythrurus.

Snakebite is an important problem in Myanmar. Regionally, bites by Eastern Russell's vipers, Daboia siamensis (Viperidae, Viperinae), and monocled cobras, Naja kaouthia are considered medically important, but those categorised as "green snake" bites are not. However, these may include bites by green pit vipers, Trimeresurus spp. (Viperidae, Crotalinae) for which no antivenom is available in Myanmar. Elsewhere in Southeast Asia, these snakes are reported to cause local and systemic envenoming. As part of the Myanmar Snakebite Project, prospective case data were collected over 3 years from five hospitals in the Mandalay region. These included 3803 snakebite cases reported from Mandalay region. Of these, 355 were listed as bites by a witnessed green-coloured snake. In 22 cases, the snakes responsible were retained and preserved, then expertly identified; 21 were medically important white-lipped pit vipers (Trimeresurus albolabris), and one as an Asian vine snake, Ahaetulla prasina (Colubridae, Ahaetuliinae) which is not of medical importance. Among confirmed Trimeresurus albolabris bites, 15/21 developed swelling of the bitten limb, and 3/21 coagulopathy, defined as a positive 20-min whole blood clotting test (20WBCT). None developed necrosis, blistering, thrombocytopenia or acute kidney injury (AKI). Of the remaining 333 patients bitten by green snakes that were not specifically identified, 241 (72%) developed swelling of the bitten limb, and 62 (19%) coagulopathy. AKI occurred in 21/333 patients, but only one required dialysis. At least 10/21 of the cases with AKI in this study were more likely to represent bites from Trimeresurus spp. than D. siamensis because the snake responsible was brought into the hospital, examined and described by the treating physician as "green-coloured". This study describes a previously unpublished case of AKI from envenoming by T. erythrurus in Yangon, and reviews cases of AKI following bites by this species and T. albolabris in Myanmar. This confirms that, at least on rare occasions, Trimeresurus spp. envenoming can cause AKI. This has important implications for snakebite management in Myanmar as the finding of local swelling, coagulopathy and AKI is generally considered pathognomonic of D. siamensis envenoming. Further collection of confirmed Trimeresurus spp. bites is required in Myanmar in order better to define the syndrome of envenoming and to assess the possible need for antivenom against Trimeresurus spp. in this country.

A Bayesian phase 2 model based adaptive design to optimise antivenom dosing: Application to a dose-finding trial for a novel Russell's viper antivenom in Myanmar.

For most antivenoms there is little information from clinical studies to infer the relationship between dose and efficacy or dose and toxicity. Antivenom dose-finding studies usually recruit too few patients (e.g. fewer than 20) relative to clinically significant event rates (e.g. 5%). Model based adaptive dose-finding studies make efficient use of accrued patient data by using information across dosing levels, and converge rapidly to the contextually defined 'optimal dose'. Adequate sample sizes for adaptive dose-finding trials can be determined by simulation. We propose a model based, Bayesian phase 2 type, adaptive clinical trial design for the characterisation of optimal initial antivenom doses in contexts where both efficacy and toxicity are measured as binary endpoints. This design is illustrated in the context of dose-finding for Daboia siamensis (Eastern Russell's viper) envenoming in Myanmar. The design formalises the optimal initial dose of antivenom as the dose closest to that giving a pre-specified desired efficacy, but resulting in less than a pre-specified maximum toxicity. For Daboia siamensis envenoming, efficacy is defined as the restoration of blood coagulability within six hours, and toxicity is defined as anaphylaxis. Comprehensive simulation studies compared the expected behaviour of the model based design to a simpler rule based design (a modified '3+3' design). The model based design can identify an optimal dose after fewer patients relative to the rule based design. Open source code for the simulations is made available in order to determine adequate sample sizes for future adaptive snakebite trials. Antivenom dose-finding trials would benefit from using standard model based adaptive designs. Dose-finding trials where rare events (e.g. 5% occurrence) are of clinical importance necessitate larger sample sizes than current practice. We will apply the model based design to determine a safe and efficacious dose for a novel lyophilised antivenom to treat Daboia siamensis envenoming in Myanmar.

Inadequate knowledge about snakebite envenoming symptoms and application of harmful first aid methods in the community in high snakebite incidence areas of Myanmar.

INTRODUCTION: Every year millions of people in developing countries suffer from snakebite, causing a large number of deaths and long term complications. Prevention and appropriate first aid could reduce the incidence and improve the health outcomes for those who suffer bites. However, many communities where snakebite is a major issue suffer from a lack of information about prevention and first aid measures that a family or community member could take to prevent severe envenoming, complications and poor outcomes. Myanmar suffers from a high burden of snakebites with a large number of deaths. As part of a health services and community development program, a community survey was conducted to identify communities' knowledge about snakebite and their sequelae, and knowledge and practice about first aid and health services use. METHOD: 4,276 rural residents of Kyaukse and Madaya townships in the Mandalay region were recruited by cluster sampling, involving random selection of 144 villages and random sampling of 30 households from each village. One adult member of each household was interviewed using a structured questionnaire. RESULTS: The incidence of snakebite was 116/100,000 people. Respondents reported 15 different types of snakes in the area, with Russell's Viper, Cobra and Green snakes as the most common. 88% of the people informed that working in the fields and forests was when most of the bites occur. A majority knew about snakebite prevention methods such as wearing long boots. However, only a few people knew about the specific symptoms caused by snakebites. Only 39% knew about the correct methods of first aid. More than 60% mentioned tourniquet as a first aid method, though this may cause significant complications such as ischaemia of the limb. 88% said that they would take a snakebite victim to a government hospital, and 58% mentioned availability of antivenom as the reason for doing this. At the same time, the majority mentioned that traditional methods existed for first aid and treatment and 25% mentioned at least one harmful traditional method as an effective measure that they might use. CONCLUSION: The community is aware of snakebites as a major public health issue and know how to prevent them. However, the high incidence of snakebites point to lack of application of preventive methods. The community recognise the need for treatment with antivenom. However, inadequate knowledge about appropriate first aid methods, and a reliance on using tourniquets require a targeted education program. Existing knowledge in communities, albeit insufficient, provides a good starting point for mass media educational campaigns.

Twelve month prospective study of snakebite in a major teaching hospital in Mandalay, Myanmar; Myanmar Snakebite Project (MSP).

The Myanmar Snakebite Project is an Australian government (Department of Foreign Affairs and Trade) supported foreign aid project in collaboration with the Myanmar government with the aim of improving outcomes for snakebite patients in Myanmar. As part of the project a case record database was established to document prospective cases of snakebite presenting to Mandalay General Hospital, in Upper Myanmar. The study period was 12 months (1-2-2016 to 31-1-2017). Snake identity was based on a mixture of identified dead snakes brought with patients, doctor's clinical opinion and patient identification. 965 patients were enrolled during the 12 month period, of whom 948 were included for analysis. The male: female ratio was 1.58:1. Most cases involved bites to the lower limbs (82.5%) and adults involved in farm work, confirming snakebite as an occupational disease in this community. Motorised transport was by far the most common form of transport to health care and most patients sought care from the health system (87.7%), not traditional healers (11.5%) as their first point of contact. The officially promoted application of a pressure pad, bandage and immobilisation as first aid for snakebite was almost never used, while most patients used some form of tourniquet (92.0%). 85.4% of cases where a snake ID was listed were bitten by Russell's vipers. Russell's viper bites were responsible for all fatalities (9.8% of cases) and all cases of Acute Kidney Injury (AKI). For all cases, clinical features included local swelling (76.5%), local pain (62.6%), AKI (59.8%), incoagulable blood (57.9%), regional lymphadenopathy (39.8%), nausea/vomiting (40.4%), thrombocytopenia (53.6%), abdominal pain (28.8%), shock (11.8%), secondary infection (8.6%), panhypopituitarism (2.1%). AKI required renal replacement therapy (RRT) in 23.9% of cases, all ascribed to Russell's viper bite. Green pit viper bites were the next most common cause of bites (7.6%) and were associated with incoagulable blood (29%) and occasionally shock (5%) and local necrosis (3%), and in one case AKI not requiring RRT. In contrast to Russell's viper bites, green pit viper bite was most likely to occur in the home (49%). Some green pit viper patients were treated with Russell's viper antivenom (15%), presumably because they had incoagulable blood, although this antivenom is not effective against green pit viper envenoming. For the entire patient group, antivenom was given in 80.5% of cases. The most common indications were presence of coagulopathy/non-clotting blood (59.8%), local swelling (47.4%), oliguria/anuria (19.8%), heavy proteinuria (19.4%). A febrile reaction to antivenom was reported in 47.9% of cases, while anaphylaxis, occurred in 7.9% of cases.