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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 This study describes a previously unpublished case of AKI from envenoming by T. erythrurus in Yangon, and reviews cases of AKI following bites by this species and T. albolabris in Myanmar.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.

The first reported snakebite by an African snake-eater, Polemon spp. (Atractaspididae, Aparallactinae); Local envenoming by Reinhardt's snake-eater, Polemon acanthias (Reinhardt, 1860). Toxicon XX, xxx. A 51-yr-old male herpetologist was bitten on the left index finger by a captive male Polemon acanthias while manually removing fragments of incompletely shed skin from the specimen. The snake sustained its bite for approximately 2 mins, advancing its jaws several times. The victim rapidly developed moderate pain, erythema, progressive edema that ultimately extended to the left wrist; a blister later developed in the wound site, as well as joint stiffness in the bitten and adjacent two fingers that limited flexion and extension. These effects regressed during the week following the bite, but recurred thereafter and were similar to the effects that developed immediately post-envenoming. There were no systemic signs or symptoms. The victim sought medical advice and was treated with broad-spectrum antibiotics, antihistamines and wound care; no laboratory investigations were conducted. He improved during the subsequent month with complete resolution in 5 and one-half weeks. This is the first documented bite by a Polemon spp. and the victim's clinical course suggests the development of local effects from venom components. The phylogenetic relationship of Polemon spp. with the burrowing asps (Atractaspis spp.) and the similarity of some of the features of this local envenoming by P. acanthias with mild/moderate envenoming by some Atractaspis spp., suggests that none of these snakes should be handled; they should be considered capable of inflicting potentially serious envenoming.

Background\ud Bites by the European adder (Vipera berus) in the UK are uncommon but potentially life threatening, and can be associated with marked limb swelling and disability. Following an interruption in Zagreb Imunološki zavod antivenom supply around 2012, the UK changed its national choice of antivenom for Vipera berus to ViperaTAb, an ovine Fab monospecific antivenom. In the absence of randomised controlled trials, we established an audit to review its use in clinical practice.\ud Methods\ud \ud A prospective audit of ViperaTAb use was conducted from March 2016 until November 2020 by the UK National Poison Information Service (NPIS). Users of the NPIS online toxicology database, TOXBASE, considering the use of antivenom for V. berus envenoming were invited to discuss the case with the on-call clinical toxicology consultant. Information was collected prospectively on indications, administration, adverse reactions and outcome of patients administered ViperaTAb antivenom.\ud Results\ud \ud One hundred and seventy patients were administered ViperaTAb antivenom over five years. One hundred and thirty-two were adults and 38 children (median age and range: 38, 2–87 years). Bites occurred across the UK, but most commonly in coastal regions of Wales and of South-West and East England. Median time to presentation was 2.1 (IQR 1.5–4.0) h and to antivenom administration from presentation was 2.0 (IQR 0.9–3.6) h. A minority of patients presented to hospital more than 12 h after being bitten (n = 19, 11.2%) or received antivenom more than 12 h after presenting to hospital (n = 17, 10.0%). Features of systemic envenoming were present in 64/170 (37.6%) patients, including 23 (13.5%) with anaphylaxis and 26 (15.3%) with hypotension (nine with both). Clinician assessment considered the initial antivenom to have been effective in 122/169 (72.2%) patients. Repeated dosing was common, occurring in 55/169 (32.5%), predominantly due to persisting or worsening local effects (46/51, 90.2%). There were three cases of probable early adverse reaction. No deaths occurred during the study. Complications of envenoming were rare but included four patients that underwent surgery, three patients each with acute kidney injury, mild coagulopathy, or thrombocytopenia (one severe). The median duration of hospital stay was 43.7 (IQR 22.5–66.5) h, longer for children than adults (52.5 vs 41.3 h).\ud Conclusion\ud \ud ViperaTAb antivenom appears to be effective and safe and should be administered as soon as possible for patients meeting clinical criteria. Patients require close observation following antivenom to detect adverse reactions and progression or recurrence of envenoming. Close collaboration with expert NPIS consultant advice can help optimise antivenom timing, ensure repeated dosing is given appropriately, and avoid unnecessary surgical intervention. All hospitals, particularly those located in areas of relatively high incidence, should stock sufficient antivenom available at short notice, 24 h a day.

The twelve Arab countries of the Middle East are inhabited by 117 species of scorpions of varying medical importance within six families. Scorpion stings are a very common occurrence throughout the region. Twenty-two scorpion species are considered to be dangerously venomous, causing potentially life threatening stings. Accessible literature in English and Arabic on scorpions, scorpion stings and available antivenoms was reviewed to document the scorpion fauna and scorpion stings in each country. Saudi Arabia, Iraq and Jordan report the highest numbers of stings and envenomings. Clinically, the most important toxins in Old World scorpion venoms are α-toxins that target voltage-gated sodium (Nav) channels at neurotoxin binding site 3, causing sympathetic excitation and the endogenous release of catecholamines that is responsible for transient, but life-threatening myocardial damage. Most victims of scorpion stings suffer severe local pain, but a few, especially children, develop systemic envenoming which, in the case of most Middle Eastern buthid species, such as Androctonus and Leiurus species, is dominated by the cardiovascular and respiratory consequences of hypercatecholinaemic myocarditis. Other syndromes include paralysis (Parabuthus leiosoma), coagulopathy (Nebo hierichonticus and Hemiscorpius species), and local tissue damage, haemolysis and acute kidney injury (H. lepturus). Early antivenom treatment is recommended but its value remains controversial. However, intensive care, with the ancillary use of vasoactive drugs such as prazosin and dobutamine, has proved effective.

Examination of 18 cobras brought to three hospitals in the Mandalay Region by patients bitten or spat at by them distinguished 3 monocled cobras (Naja kaouthia) and 15 Mandalay spitting cobras (N. mandalayensis), based on their morphological characteristics. We confirm and extend the known distributions and habitats of both N. mandalayensis and N. kaouthia in Upper Myanmar. Clinical symptoms of local and systemic envenoming by N. mandalayensis are described for the first time. These included local swelling, blistering and necrosis and life-threatening systemic neurotoxicity. More information is needed about the clinical phenotype and management of bites by N. mandalayensis, the commoner of the two cobras in Upper Myanmar. Since the current cobra antivenom manufactured in Myanmar has lower pre-clinical efficacy against N. mandalayensis than N. kaouthia, there is a need for more specific antivenom therapy.

King Cobra (Ophiophagus hannah) bite is well-known for its potentially fatal neurotoxicity. However, fatalities still occur, despite specific antivenom and respiratory support. Cardiovascular disturbances, which have attracted little attention in published reports of O. hannah envenoming, could contribute to fatality. We present two cases of confirmed O. hannah envenoming in Southern Vietnam in which there were cardiac abnormalities including arrhythmias and electrocardiographic changes, as well as elevated markers of myocardial damage. Cardiac pacing was required. One patient developed critical multi-organ dysfunctions partly explained by extensive necrotizing fasciitis/myositis originating from an Aeromonas sobria wound infection. This resulted in rhabdomyolysis, disseminated intravascular coagulation and acute kidney injury. Specific antivenom reversed neurotoxic effects of envenoming. Additional therapeutic interventions included antibiotics, surgical debridement, continuous renal replacement therapy and therapeutic plasma exchange. Both patients eventually made full recoveries. Apart from the critical problem of rapidly evolving and severe neurotoxicity, our case reports also emphasises the risk of cardiotoxic envenoming, and the complications of an overwhelming secondary bacterial wound infection. We suggest a practical approach to diagnosis and management.

Fifty-two confirmed cases of snakebites in Kuwait were recorded during 2015–2019. The male:female ratio was almost 2:1 and 84.6% of the victims were between 1 and 20 y of age and 14.4% were >30 y. Snakebites peaked in October (23.1%) and July (17.3%), with the lowest number of recorded cases in March.

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., Author summary Snakebite envenoming is one of the most neglected tropical diseases considering its burden of mortality and morbidity. Antivenoms are the only known effective treatment for snake-bite envenoming but are frequently responsible for high rates of adverse reactions. Clinical development of antivenoms rarely follows the iterative phases of clinical development applied to other drugs. Dosing is typically based on pre-clinical testing. Here we propose a Bayesian model based adaptive design for phase 2 clinical trials aiming to determine the optimal dose of antivenom needed for treatment of snakebite envenoming. Optimality is defined using safety and efficacy thresholds contextual to the study. This design can be applied to all antivenoms which have binary efficacy and toxicity endpoints. Our design formally specifies a desired efficacy and a maximum tolerated toxicity. We use simulation studies to characterise adequate sample sizes to determine an approximately optimal dose under different scenarios. The simulation studies highlight the advantages of a model based design over simpler rule based alternatives. This design will be used to determine an effective and safe dose of the new lyophilised viper antivenom currently in use to treat Russell’s viper envenoming in Myanmar.

Attacks by wild and domesticated animals are increasing worldwide. They are best prevented by taking local advice about minimizing exposure. Injuries usually occur in places remote from medical care. They may involve extensive trauma, haemorrhagic shock, and a high risk of bacterial contamination. First aid consists of resuscitation, control of bleeding and perforating injuries, intravenous fluid replacement, and rapid evacuation to hospital for emergency surgery and treatment of infection. In hospital, specific antivenom (hyperimmune equine or ovine immunoglobulins) is given if there is evidence of systemic or severe local envenoming. Early anaphylactic or pyrogenic reactions and late serum sickness antivenom reactions are common but not predictable by hypersensitivity tests.

This chapter covers orf and milker’s nodule, which are characteristic nodular skin lesions caused by parapox viruses of sheep and goats, or cattle, respectively. These viruses are epitheliotropic and able to suppress the host’s immune response. The infections are occupational zoonoses of people working with ruminants. A single or small number of somewhat painful pustules develops, usually on the hand, at the site of contact with an animal’s lesions. Fever is unusual, but local lymphadenopathy, erythema multiforme, or secondary infection may occur. Spontaneous resolution within 6 weeks is usual. Multiple, giant lesions may develop in the immunosuppressed. Topical cidofovir is effective in severe cases.

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. less 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 studies.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 Russell’s viper 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 the optimal dose after fewer patients than the rule based design. Open source code for the simulations can be used to calculate sample sizes under a priori beliefs of efficacy and toxicity.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.Author summarySnakebite envenoming is one of the most neglected tropical diseases relative to its mortality and morbidity. Antivenoms are the only known effective treatment for snake-bite envenoming but are frequently responsible for high rates of adverse reactions. Clinical development of antivenoms rarely follows the iterative phases of clinical development applied to other drugs. Dosing is typically based on pre-clinical testing.Here we propose a Bayesian model based adaptive design for clinical trials aiming to determine the optimal dose of antivenom needed. Optimality is defined using safety and efficacy thresholds contextual to the study. This design can be applied to all antivenoms which have binary efficacy and toxicity endpoints. Our design formally specifies a desired efficacy and a maximum tolerated toxicity. We use simulation studies to characterise the sample size necessary to determine the optimal dose in different scenarios. The simulation studies highlight the advantages of a model based design over simpler rule based alternatives. We intend to use this design to determine an effective and safe dose of the new lyophilised viper antivenom currently in use to treat Russell’s viper envenoming in Myanmar.

The World Health Organization call to halve global snakebite deaths by 2030 will require substantial progress in India. We analyzed 2833 snakebite deaths from 611,483 verbal autopsies in the nationally representative Indian Million Death Study from 2001 to 2014, and conducted a systematic literature review from 2000 to 2019 covering 87,590 snakebites. We estimate that India had 1.2 million snakebite deaths (average 58,000/year) from 2000 to 2019. Nearly half occurred at ages 30–69 years and over a quarter in children < 15 years. Most occurred at home in the rural areas. About 70% occurred in eight higher burden states and half during the rainy season and at low altitude. The risk of an Indian dying from snakebite before age 70 is about 1 in 250, but notably higher in some areas. More crudely, we estimate 1.11–1.77 million bites in 2015, of which 70% showed symptoms of envenomation. Prevention and treatment strategies might substantially reduce snakebite mortality in India.

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., Author summary Snakebite is a major public health problem, particularly in developing countries in the tropics, and every year millions of people suffer from snakebite causing a large number of deaths and long term complications. Communities’ knowledge about snakebite prevention practices and appropriate basic first aid could reduce the number of snakebites and improve the health outcomes for those who suffer bites. However, many communities where snakebite is a major issue may lack information about prevention and first aid measures that a family or community member could take to prevent severe complications and poor outcomes. Myanmar suffers from a high burden of snakebites with a large number of deaths. We conducted a community survey in two townships to identify communities’ knowledge about snakebite prevention, first aid and health services use. The survey informed that a large majority of people were aware that working in the fields and forests was when most of the bites occur. Similarly, a majority has the knowledge about snakebite prevention methods such as wearing long boots. However, the majority did not know about the correct methods of first aid, with many people mentioning tourniquet as a first aid method. While the community is aware of how to prevent snakebites, the fact that number of snakebites is high points to lack of application of those preventive methods. The inadequate knowledge about appropriate first aid methods with a reliance on using tourniquets informs about the need for public health education programs.

This chapter provides the reader with essential information on venomous animals, and the risk they may pose in many humanitarian settings, especially in rural, remote, and tropical settings. Humanitarian providers will have the responsibility of preventing and treating venomous bites and stings both in the local community as well as among their team members, and this chapter provides the necessary information to help guide planning, decision-making, and management.

The false water cobra (Hydrodynastes gigas) is a non-front-fanged colubroid snake frequently exhibited in zoos, and maintained by amateur collectors. Little detailed documentation regarding the time-course of symptoms development and the consequences of their bites to humans has been published. Reported here is a case of envenoming in a 25 yo male that occurred after the bite of a juvenile H. gigas. The victim was bitten on the fourth digit of the left hand while processing the snake for sex determination, and the snake remained attached to the digit for approximately 30 s; there was no jaw advancement. Within 5 min, intense local pain developed, and at 4hr post bite the entire dorsal aspect of the hand was significantly edematous, The local effects progressed and involved the entire forearm, and the local pain referred to the axillary region. Mild paresthesia and local blanching ("pallor") were noted in the affected digit, but resolved within 7 days. The clinical course in the patient showed that moderate localized symptoms may result from the bite of a juvenile H.gigas.

The collapsed patient - Medical emergencies - Resuscitation in the wilderness - Basic life support (CPR) - Choking - Recovery position - Shock - Management of the shocked patient - Types of shock - Chest pain - Shortness of breath (dyspnoea) - Coma - Headache - Delirium/confusion - Convulsions - Diabetic emergencies - Gastrointestinal bleeding - Fever

Snakebite envenoming is a serious problem in Myanmar. The great majority of snakebite in this country is due to Russell's Viper (Daboia siamensis). For many years, the Burma Pharmaceutical Industry has produced a monovalent antivenom to Russell's Viper in horses. At present, the only way of determining the level of antibody against D. siamensis venom in hyperimmune horse serum is to perform venom neutralisation tests in mice. In this study, we describe the development of an in vitro ELISA assay to estimate neutralising capacity of horse serum. We found a strong correlation between the ELISA assay and the venom neutralisation test in mice (r = 0.982). The assay is robust and has sufficient sensitivity (92%) and specificity (96%) to replace the venom neutralisation test in mice during the immunisation phase in horses.

Introduction The global incidence of snakebite is estimated at more than 2.5 million cases annually, with greater than 100,000 deaths. Historically, Myanmar has one of the highest incidences of venomous snakebites. In order to improve the health outcomes of snakebite patients in Myanmar, access to accurate snakebite incidence data is crucial. The last population-based study in Myanmar was conducted more than a decade ago. In 2014, the Ministry of Health and Sports data from health facilities indicated an incidence of about 29.5 bites/ 100,000 population/year (a total of 15,079 bites). Since data from health facilities lack information about those who do not seek health care from government health services, a new population-based survey was conducted in 2 rural areas of Mandalay region. The survey data were compared to those obtained from healthcare services. Method 4,276 rural respondents in Kyaukse and Madaya townships in Mandalay Division were recruited using cluster sampling that involved random selection of 150 villages and random sampling of 30 households from each village. One adult member of each household was interviewed using a structured questionnaire. Results One respondent from each of 4,276 households represented 19,877 residents from 144 villages. 24 people in these households had suffered snakebite during the last one year giving an annual incidence of 116/100,000. During the last ten years, 252 people suffered snakebites. 44.1% of the victims were women. 14% of the villages reported 4 or more bites during the last ten years, whereas 27% villages reported no snakebites. 92.4% of the victims recovered fully, 5.4% died, and 2% suffered long term health issues. One victim was reported to have died from causes unrelated to the snakebite. While there was no statistically significant difference between outcomes for children and adults, 4 of 38 of those under 18 years of age died compared to 7 of 133 adults between 19 to 40 years of age. Conclusion This incidence reported by the community members points to substantially more snakebites than the number of snakebite patients attending health facilities. This higher incidence points to the need for a nation-wide population-based survey, community education about gaining access to care where antivenom is available, and to the potential need for a larger supply of antivenom and expansion of medical care in rural areas., Author summary Snakebite is a major health issue affecting large numbers of people, particularly in tropical developing countries. Myanmar has one of the highest incidences of venomous snakebite in the world. Considering changes in demography, development, agricultural practices, knowledge about prevention and preventive practices, regular and accurate assessment of incidence is needed in order to improve public health programs and health services provision to improve health outcomes for snakebite patients. For that purpose, we conducted a large population based survey in Mandalay, which is one of the seven high incidence regions in Myanmar. The survey indicated a substantially higher incidence of snakebites than that suggested by the number of snakebite victims attending health care centres and hospitals. This higher incidence of snakebite has implications for community health service planning, scale of production of antivenom, and the need to improve access to health care centres or hospitals where antivenom is available, and suggests a need for community health education regarding appropriate 1st aid.

International audience; The aim of this review is to guide clinicians in the practical management of patients suffering from rabies encephalomyelitis. This condition is eminently preventable by modern post-exposure vaccination, but is virtually always fatal in unvaccinated people. In the absence of any proven effective antiviral or other treatment, palliative care is an imperative to minimise suffering. Suspicion of rabies encephalomyelitis depends on recognising the classic symptomatology and eliciting a history of exposure to a possibly rabid mammal. Potentially treatable differential diagnoses must be eliminated, notably other infective encephalopathies. Laboratory confirmation of suspected rabies is not usually possible in many endemic areas, but is essential for public health surveillance. In a disease as agonising and terrifying as rabies encephalomyelitis, alleviation of distressing symptoms is the primary concern and overriding responsibility of medical staff. Calm, quiet conditions should be created, allowing relatives to communicate with the dying patient in safety and privacy. Palliative management must address thirst and dehydration, fever, anxiety, fear, restlessness, agitation, seizures, hypersecretion, and pain. As the infection progresses, coma and respiratory, cardiovascular, neurological, endocrine, or gastrointestinal complications will eventually ensue. When the facilities exist, the possibility of intensive care may arise, but although some patients may survive, they will be left with severe neurological sequelae. Recovery from rabies is extremely rare, and heroic measures with intensive care should be considered only in patients who have been previously vaccinated, develop rabies antibody within the first week of illness, or were infected by an American bat rabies virus. However, in most cases, clinicians must have the courage to offer compassionate palliation whenever the diagnosis of rabies encephalomyelitis is inescapable.

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., Highlights • Reports 12 month prospective observational study of snakebite patients at Mandalay General Hosp. • Snakebite was an occupational disease of farm workers, tourniquets the most common first aid. • Russell's viper (RV) responsible for most bites, causing coagulopathy, thrombocytopenia, AKI. • Green pit viper bites were the next most common, potentially causing diagnostic confusion with RV.

Background Snakebite is a major public health problem in many developing countries. Farmers are particularly exposed to snakes, and due to their rural location often experience delays in accessing formal healthcare. The reasons to use traditional healers may include difficulties in accessing formal healthcare, certain beliefs about snakes and snake venom, tradition, and trust in the capacity of traditional healers. Traditional healing, however, may have serious consequences in terms of delays or added complications. There is little in-depth current information about the reasons for its continued use for snakebite. As part of a health services development project to improve health outcomes for snakebite patients, community attitudes to the use of traditional healers were explored in the Mandalay region of Myanmar. Methodology & findings With the objective of learning from local communities, information was generated in three communities using participatory appraisal methods with the communities, and focus group discussions with the local healthcare staff. Many snakebite victims in these communities use traditional healing. Reasons include transport difficulties, low cost for traditional healing, inadequacy of anti-snake venom in the formal healthcare sector, and traditional beliefs, as traditional healing practices are rooted in many cultural and traditional factors. The communities reported that even if access to medical care were improved, traditional healing would continue to be used. Conclusion These findings point to the need for working with traditional healers for prevention, appropriate first aid and timely access to effective treatment for snakebite., Author summary Snakebite is a major health issue that affects many people, particularly young poor farmers in developing countries in the tropics. Many patients suffer poor outcomes due to inadequate or delayed access to effective treatment. A large number still use traditional healers. Often patients visit traditional healers before accessing formal health care; thus incurring delays in receiving antivenom (AV) needed to treat envenoming. In other cases, traditional healing methods may themselves cause complications. In Myanmar, while most patients now access formal medical care, many also use traditional healers. We consulted communities in three rural areas in the Mandalay region and found that the reasons for using traditional healers include difficulties with transportation, cost, inadequacy of AV in the formal health sector, and trust in traditional healing within the context of longstanding tradition. These findings point to the need for working with the traditional healers as they could be effective agents to encourage prompt use of formal healthcare.

Nature Reviews Disease Primers 3, 17063 (2017) In the original version of this article, it was incorrectly stated that tetanus toxoid boosts the immunity against snakebites (Table 2). This has now been corrected to ‘To boost immunity against tetanus toxin in all bite cases’

Australian toxinology can contribute more to helping tropical developing countries where snakebites are a serious problem

Louse-borne relapsing fever and tick-borne relapsing fever are characterized by repeated episodes of high fever separated by afebrile periods. They are caused by Borrelia spirochaetes distinct from those responsible for Lyme borrelioses. Untreated patients may suffer as many as five (louse-borne relapsing fever) or ten (tick-borne relapsing fever) febrile relapses of decreasing severity. B. myamotoi is much less likely to relapse. Humans are the sole reservoir of epidemic louse-borne relapsing fever caused by B. recurrentis and transmitted by body lice (Pediculus humanus corporis). Endemic tick-borne relapsing fevers are caused by at least 17 different Borrelia species and have their own particular species of soft Ornithodoros, or, in the case of B. myamotoi and B. lonestari, hard Ixodes or Ablyomma tick vectors that also act as reservoirs. Transmission transplacentally, or by needlestick, blood transfusion, or laboratory accident is also possible.

Snakebite is predominantly an occupational disease affecting poor rural farmers in tropical regions and was recently added to the World Health Organisation list of Neglected Tropical Diseases (NTD). We document an overview of methodologies developed and deployed in the Myanmar Snakebite Project, a foreign aid project largely funded by the Australian Government, with the core aim to “improve outcomes for snakebite patients”. A multidisciplinary team of experts was assembled that worked in a collaborative manner with colleagues in Myanmar, first to identify problems related to managing snakebite and then develop interventions aimed to improve selected problem areas. A broad approach was adopted, covering antivenom production, antivenom distribution and health system management of snakebite. Problems identified in antivenom production included poor snake husbandry resulting in poor survival of captive specimens, lack of geographical diversity; poor horse husbandry, resulting in high mortality, inadequate stock acquisition protocols and data collection, and inappropriate immunisation and bleeding techniques; and inadequate production capacity for freeze dried antivenoms and quality control systems. These problems were addressed in various ways, resulting in some substantial improvements. Antivenom distribution is being reorganised to achieve better availability and utilisation of stock. Health system management of snakebite was assessed across all levels within the area selected for the study, in Mandalay region. A comprehensive community survey indicated that hospital statistics substantially underestimated the snakebite burden, and that access to care by local villagers was delayed by transport and cost issues compounded by lack of antivenom at the most peripheral level of the health service. A health system survey confirmed under-resourcing at the local village level. Prospective case data collection initiated at tertiary hospitals indicated the extent of the snakebite burden on health resources. Interventions initiated or planned include training of health staff, development of a core of senior trainers who can “train the trainers” nationwide in a sustainable way, development and deployment of management guidelines and algorithms for snakebite and a distribution of solar powered fridges to remote health facilities to allow storage of antivenom and prompt treatment of snakebite cases before transfer to major hospitals, thereby reducing the “bite to needle” time., Highlights • Documents an international aid project in Myanmar to improve outcomes for snakebite patients. • 3 focus areas; improving antivenom production, availability, and care of snakebite patients. • Emphasizes a broad approach and importance of inter-ministerial government collaboration. • Emphasizes sustainable improvements through health services strengthening and training. • Community involvement, education and use of local community surveys are described and advocated.

Vaccine regimens using 0.1 ml human diploid cell strain vaccine (HDCSV) given intradermally (id) in single and multiple sites, or with aluminum hydroxide adjuvant given subcutaneously (sc), were compared with the regimens of HDCSV and Semple vaccine currently suggested by WHO. Some groups were also given human rabies-immune globulin (HRIG). Neutralising antibody titres were monitored for 3 months. Antibody was detected earliest in subjects given 0.1 ml HDCSV id at each of eight sites. The highest antibody titres from day 14 onwards were found after intramuscular (im) administration of HDCSV, but the multiple-site id regimen, which requires only one quarter of the volume of vaccine required for the im regimen, gave similar results, provided that a booster was given on day 91. This finding suggests that a treatment schedule based on this regimen would be suitable for post-exposure prophylaxis. Adjuvanted vaccine gave similar results to the same amount of antigen given id. Semple vaccine produced the lowest titres. HRIG, given at the high dose of 40 IU per kg, suppressed the antibody response to some of the regimens.

The bites of six species of venomous elapid snakes in Central Province Papua New Guinea produce similar clinical syndromes. Optimal management of envenomed patients involves the use of monospecific antivenom. In this study, Venom Detection Kits (VDKs) (CSL Diagnostics, Melbourne) were used to try to make a specific diagnosis in envenomed patients at their admission. VDKs detected venom in admission bite site swabs from 39 to 46 patients (85%). Thirty-eight of these patients were shown to have been bitten by taipans. In all cases where venom was detected by the VDK, this correlated with subsequent laboratory enzyme immunoassay results. Selective use of VDKs in Central Province could allow more widespread use of monospecific antivenoms and produce considerable financial savings.

1. H.p.l.c. methods are described for the measurement of pyrimethamine and sulphadoxine in small volumes of plasma dried on filter paper strips. 2. Pyrimethamine/sulphadoxine (Fansidar, Hoffman LaRoche) was given by mouth and by intramuscular injection to children with uncomplicated falciparum malaria but with high parasitaemia (n = 8 for both routes; pyrimethamine 1.25 mg kg-1, sulphadoxine 25 mg kg-1). 3. Plasma concentrations of pyrimethamine and sulphadoxine associated with synergistic effects against pyrimethamine-resistant strains of Plasmodium falciparum in vitro were achieved within 1 h of administration and were maintained beyond the end of sampling. 4. After both oral and parenteral administration the plasma concentrations of both compounds were lower than those predicted by data from healthy subjects. 5. Areas under the plasma concentration-time curves of sulphadoxine after oral and i.m. administration did not differ significantly, although maximum plasma drug concentrations were higher after the i.m. route (P = 0.03). 6. The AUC values of pyrimethamine did not differ significantly between the two routes of administration. However, after i.m. administration AUC(0,24 h) values were smaller (P = 0.03), and the time to maximum plasma drug concentration (tmax) was longer (P = 0.004) than when the drug was given orally.

In Kerala, south-western India, five patients developed systemic envenoming after bites by hump-nosed pit vipers (Hypnale hypnale), proved by identification of the snakes responsible. Two of the dead snakes had been misidentified as saw-scaled vipers (Echis carinatus), while three had remained unidentified. Symptoms of local envenoming were pain, swelling, haemorrhagic blistering, bruising and regional lymphadenopathy. Systemic symptoms included headache, nausea, vomiting and abdominal and chest pain. There was evidence of haemostatic dysfunction (coagulopathy, fibrinolysis, thrombocytopenia or spontaneous systemic haemorrhage) in all cases and of microangiopathic haemolysis in two. Two patients were haemodialysed for acute renal failure, one of whom developed pulmonary oedema requiring mechanical ventilation. In India, H. hypnale has not previously been regarded as a cause of frequent or potentially dangerous envenoming. Its medical importance has been overlooked throughout its geographical range, probably because of confusion with other small species. No specific antivenom exists, yet most patients are treated with non-specific antivenoms, risking reactions without hope of benefit. An effective antivenom is urgently needed in south India and in Sri Lanka, where this species is also a common cause of bites.

Severe falciparum malaria usually occurs in children, but also occurs in nonimmune migrants or partially immune adults in areas of unstable transmission. We have studied prospectively 70 adult patients with strictly defined severe malaria from the south coast of Papua New Guinea where malaria transmission is not intense. Only 19 (27.1%) were migrants from areas where malaria transmission does not occur; many other patients were periurban dwellers who had become infected after visits to their home villages. The most common clinical features were jaundice or hepatic dysfunction, impaired consciousness, renal failure, cerebral malaria, and anemia. Hypoglycemia was common following treatment with quinine. The overall case fatality rate was 18.6%; renal failure and cerebral malaria in particular were associated with a poor outcome. Reduction in mortality might be achieved by aggressive therapy of renal failure with earlier institution of dialysis; the use of preventive measures for immigrants or urban dwellers returning to high transmission areas might reduce the incidence of this dangerous disease.

A prospective study was designed to define epidemiologic and clinical features of krait bites to improve diagnosis, management, and prevention. Among 762 cases of venomous snake bites admitted to 10 Sri Lankan hospitals in which the snake responsible was brought and identified, 88 (11.5%) were caused by common kraits (Bungarus caeruleus). Bites were: most frequent in September through November. Distinctive features of B. caeruleus bites (compared with bites by other species in parentheses) were bitten while sleeping on the ground, 100% (1%); indoors, 100% (49%); between 2300 and 0500 hours, 100% (3%). Only 13% of krait victims were bitten on their lower limbs (82%), only 9% had local swelling (in all cases mild) at the site of the bite (93%), 64% developed respiratory paralysis (2%), and 91% experienced (often severe) abdominal pain (10%). Case fatality was 6% (3%). This distinctive pattern of epidemiology and symptoms will aid clinical recognition (syndromic diagnosis) and prevention of krait bite envenoming.

Russell's viper, Vipera russelli (Shaw), is distributed erratically in 10 south Asian countries and is a leading cause of fatal snake bite in Pakistan, India, Bangladesh, Sri Lanka, Burma and Thailand. In Burma it has been the 5th most important cause of death. Its venom is of great interest to laboratory scientists and clinicians. The precoagulant activity of the venom was used by Macfarlane and others to elucidate the human clotting cascade. Up to 70% of the protein content is phospholipase A2, present in the form of at least 7 isoenzymes. Possible clinical effects of the enzyme include haemolysis, rhabdomyolysis, pre-synaptic neurotoxicity, vasodilatation and shock, release of endogenous autacoids and interaction with monoamine receptors. Russell's viper bite is an occupational hazard of rice farmers throughout its geographical range. Defibrination, spontaneous haemorrhage, shock and renal failure develop with frightening rapidity. In several countries, Russell's viper bite is the commonest cause of acute renal failure. There is a fascinating geographical variation in the clinical manifestations, doubtless reflecting differences in venom composition. Conjunctival oedema is unique to Burma, acute pituitary infarction to Burma and south India, and rhabdomyolysis and neurotoxicity to Sri Lanka and south India. Treatment with potent specific antivenom rapidly controls bleeding and clotting disorders, but may not reverse nephrotoxicity and shock. Causes of death include shock, pituitary and intracranial haemorrhage, massive gastrointestinal haemorrhage and acute tubular necrosis or bilateral renal cortical necrosis. The paddy farmer and the Russell's viper coexist in fragile symbiosis. The snake controls rodent pests but inevitably interacts with man, often with mutually disastrous results.

Apparently, the United Kingdom had been free of indigenous rabies since 1902. However, in 1996, a rabies-infected Daubenton’s bat (Myotis daubentonii) was found at Newhaven on the south coast of England. It seemed possible that this sick bat had been carried in by boat or blown across the Channel by prevailing winds. In 2002, an infected juvenile bat of the same species was found on the Lancashire Canal, which runs between Preston and Tewitfield in northwestern England. Both the bat’s age and location favored the possibility that it had acquired rabies in England. In both these cases, the rabies-related virus involved was European bat lyssavirus (EBLV) type 2a (Whitby et al., 2000; Johnson et al., 2002). EBLV 2 had been implicated in three human deaths from rabies in mainland Europe (Lumio et al., 1986; World Health Organisation 1987; Roine et al., 1988). On November 19, 2002, a 55-year-old male natural history artist was admitted to hospital in Aberdeen, Scotland, complaining of 5-days’ increasing pain in the left arm, paraesthesiae of both arms, and dysphagia. He was found to be feverish (38.5 C), inappropriately disinhibited, dysarthric, with nystagmus, areflexic arms, ataxia, and dysaesthesia of the left arm. CT and MRI of the brain were essentially normal, as was the cerebrospinal fluid (CSF). On the fifth day of his hospital admission, he became acutely confused, aggressive, and agitated, and his Glasgow Coma Score declined to 6. The repeat CT scan was normal, but the CSF protein was elevated and there was a mild lymphocyte pleocytosis. The next day there was further deterioration, with pulmonary collapse, respiratory failure, a further decline in Glasgow Coma Score to 3, excessive salivation, and flaccid quadriplegia with extensor plantar responses. He died on the 14th day of hospital admission. A more detailed history revealed that he had been bitten frequently by bats in the course of his work as a bat conservationist in Angus, Scotland. Most recently, he had been bitten on the left hand 19 weeks earlier by a Daubenton’s bat. Although the Department of Health had recommended pre-exposure vaccination against rabies for licensed bat handlers (UK Health Departments, 1996), the patient had apparently refused this protection. PCR revealed the presence of EBLV type 2a in saliva

A group of seven patients with increased transradiancy of one lung included four with chronic bronchitis. The function of the two lungs combined was assessed by measurement of the lung volumes, airway resistance, and carbon monoxide uptake at rest, and by measurement of pulmonary ventilation, gas exchange, blood gases, and cardiac output at rest and during steady state exercise. The contribution of the hypertransradiant lung to the overall functional abnormalities at rest was estimated using a radioactive gas technique. All the patients had airway obstruction. Pulmonary gas exchange was only mildly affected at rest because of equal reduction of ventilation and perfusion in the abnormal lung, but during exercise ventilation-perfusion inequality increased in some of the patients. Cardiac output was low in five patients during exercise and in four there was excessive lactate production. The greatest physiological abnormalities were seen in two of the chronic bronchitics who had abnormalities of ventilation and perfusion in both lungs. We suggest that a pulmonary vascular abnormality resulting in reduced cardiac output, as well as ventilatory impairment due to airway obstruction, may contribute to the limited exercise capacity of these patients.

The mechanisms of haemostatic failure were studied in 87 patients bitten by the Papuan taipan (Oxyuranus scutellatus canni). Eighty (92%) had evidence of a coagulopathy on laboratory testing; 36 (41.4%) developed spontaneous systemic bleeding, although this was rarely of clinical significance. Coagulation assays in 48 completely defibrinated patients showed marked reductions in factors V and VIII and reductions in factors II, IX, XI, XII and XIIIA. There was a reduction in plasminogen and alpha 2-antiplasmin levels and both total and cross-linked fibrin(ogen) degradation products (FDP) levels were elevated. The mean platelet count was initially decreased and fell further during admission. Similar but less severe changes were seen in patients who were mildly defibrinated. Following treatment with antivenom, fibrinogen levels rose rapidly and coagulability was restored within 6-12 h in 93% of patients. These abnormalities may be primarily attributable to the prothrombin activator present in taipan venom, but it is likely that other uncharacterized venom components contributed.

In Papua New Guinea cryptococcal meningitis occurs predominantly in immunocompetent patients in whom Cryptococcus neoformans var, gattii is implicated in 95% of cases. Ocular complications are common. We have reviewed ophthalmic findings in 82 immunocompetent patients and have attempted to identify those features of the disease that predict an unfavourable visual outcome. Visual loss occurred in 52.6% of survivors and was associated with optic atrophy following optic disc swelling in 60.9%. Progression of disc swelling to optic atrophy was predicted by the presence of an abducens palsy (P = 0.049) and cerebrospinal fluid (CSF) cryptococcal antigen titres > 1:1024 (P = 0.036). Raised intracranial pressure (defined as opening CSF pressure > or = 300 mm on admission) was not associated with visual loss. Vision deteriorated in 17.3% of patients despite anticryptococcal therapy and in 3.7% it followed curative therapy. The high rate of visual loss in immunocompetent patients with C. neoformans var. gattii infection contrasts with others' experience of immunosuppressed patients with C. neoformans var. neoformans infection, in whom visual loss was rare. This difference may reflect immune mediated optic nerve dysfunction in C. neoformans var. gattii meningitis caused by either compression due to arachnoid adhesions or oedema and inflammatory cell-mediated damage.

In a double-blind cross-over trial of disodium cromoglycate on 11 patients nine were symptomatically improved, and in all of these daily measurements of peak expiratory flow increased. The forced expiratory volume in the first second and specific airway conductance did not increase in all patients. In most cases the average values for residual volume and functional residual capacity fell; exercise capacity and ventilation did not change, but the pulse rate on exercise was lower. It is suggested that the changes produced by disodium cromoglycate are worth while.

During a prospective study of 147 patients with snakebite presenting to a rural South African hospital, 13 of 17 patients (76%) treated with South African Institute for Medical Research (SAIMR) polyvalent antivenom experienced potentially severe early (anaphylactoid) reactions. The most common reaction was generalized urticaria (12; 71%), but 3 cases of angio-oedema (18%), 2 of bronchospasm (12%), and 2 of hypotension (12%) were also observed. Reactions were controlled with adrenaline, antihistamines, and resuscitation. All patients fully recovered from envenoming although the full dose of antivenom was not given to most. Indications for the use of this antivenom should be reconsidered and patients should be given antivenom in a high care setting if possible. Use of antivenom by lay people outside hospital should be discouraged and antivenom manufacturing processes could usefully be reviewed.

Young African children with severe malaria are given quinine using a regimen designed for Thai adults. We measured quinine in the blood, plasma and plasma water of young children in Kenya after rapid intravenous and intramuscular dosing, and calculated the therapeutic range of unbound quinine. The peak plasma quinine concentration after rapid intravenous dosing was 12.3 +/- 3.7 mg/L (mean +/- SD), 43% higher than in adults given the same regimen previously; this was due to a smaller apparent volume of distribution in the children. The therapeutic range of unbound quinine was calculated as 0.2-2.0 mg/L. Simulations of unbound quinine were made for the standard quinine regimen: unbound drug concentrations rose above the therapeutic range after each dose. The possible risks of quinine-induced visual impairment are discussed. Alternative, lower dose regimens for young African children with severe malaria are described.

Five patients were bitten by the Malayan krait Bungarus candidus (Linnaeus) in eastern Thailand or north western Malaya. Two patients were not envenomed but the other three developed generalised paralysis which progressed to respiratory paralysis in two cases, one of which ended fatally. One patient showed parasympathetic abnormalities. Anticholinesterase produced a dramatic improvement in one patient. Another patient probably benefited from paraspecific antivenom. The efficacy of antivenoms and adjuvants such as anticholinesterases in patients with neurotoxic envenoming requires further study.