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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.

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.

Snakebite envenoming is a common but neglected public health problem, particularly in impoverished rural regions of sub-Saharan Africa, Asia and Latin America. The only validated treatment for this condition is passive immunotherapy with safe and effective animal-derived antivenoms. However, there is a long-lasting crisis in the availability of these life-saving medications, particularly in sub-Saharan Africa and parts of Asia. We herein advocate a multicomponent strategy to substantially improve the availability of safe and effective antivenoms at the global level. This strategy is based on: (i) preparing validated collections of representative venom pools from the most medically dangerous snakes in high-risk regions of the world; (ii) strengthening the capacity of national antivenom manufacturing and quality control laboratories and their regulatory authorities and establishing new facilities in developing countries through technology transfer, as an integral part of efforts to develop their biological products industry; (iii) getting established laboratories to generate antivenoms for various regions of the world; and (iv) getting governments and relevant organizations to give snakebite envenoming due recognition within national and international public health policy frameworks. These ways of making antivenom available should be complemented by actions to improve health information systems, the accessibility of antivenoms, the training of medical and nursing staff, and community-based education. Such a multicomponent strategy involving stakeholders on many levels could help consolidate sustainable improvements in antivenom availability worldwide.

BACKGROUND:Snakebite poisoning is a significant medical problem in agricultural societies in Sub Saharan Africa. Antivenom (AV) is the standard treatment, and we assessed the cost-effectiveness of making it available in 16 countries in West Africa. METHODS:We determined the cost-effectiveness of AV based on a decision-tree model from a public payer perspective. Specific AVs included in the model were Antivipmyn, FAV Afrique, EchiTab-G and EchiTab-Plus. We derived inputs from the literature which included: type of snakes causing bites (carpet viper (Echis species)/non-carpet viper), AV effectiveness against death, mortality without AV, probability of Early Adverse Reactions (EAR), likelihood of death from EAR, average age at envenomation in years, anticipated remaining life span and likelihood of amputation. Costs incurred by the victims include: costs of confirming and evaluating envenomation, AV acquisition, routine care, AV transportation logistics, hospital admission and related transportation costs, management of AV EAR compared to the alternative of free snakebite care with ineffective or no AV. Incremental Cost Effectiveness Ratios (ICERs) were assessed as the cost per death averted and the cost per Disability-Adjusted-Life-Years (DALY) averted. Probabilistic Sensitivity Analyses (PSA) using Monte Carlo simulations were used to obtain 95% Confidence Intervals of ICERs. RESULTS:The cost/death averted for the 16 countries of interest ranged from $1,997 in Guinea Bissau to $6,205 for Liberia and Sierra Leone. The cost/DALY averted ranged from $83 (95% Confidence Interval: $36-$240) for Benin Republic to $281 ($159-457) for Sierra-Leone. In all cases, the base-case cost/DALY averted estimate fell below the commonly accepted threshold of one time per capita GDP, suggesting that AV is highly cost-effective for the treatment of snakebite in all 16 WA countries. The findings were consistent even with variations of inputs in 1-way sensitivity analyses. In addition, the PSA showed that in the majority of iterations ranging from 97.3% in Liberia to 100% in Cameroun, Guinea Bissau, Mali, Nigeria and Senegal, our model results yielded an ICER that fell below the threshold of one time per capita GDP, thus, indicating a high degree of confidence in our results. CONCLUSIONS:Therapy for SBE with AV in countries of WA is highly cost-effective at commonly accepted thresholds. Broadening access to effective AVs in rural communities in West Africa is a priority.

BACKGROUND:Snakebite envenoming (SBE) is a major problem in rural areas of West Africa (WA). Compared to other Neglected Tropical Diseases (NTD), the public health burden of SBE has not been well characterized. We estimated the impact of snakebite mortality and morbidity using the Disability Adjusted Life Years (DALYs) metrics for 16 countries in WA. METHODS:We used the reported annual number of SB deaths and mean age at time of SB and converted these into years of life lost (YLL). Similarly, the years of life lived with disability (YLD) were estimated by multiplying the number of amputations by the respective disability weight of 0.13. RESULTS:In WA, the annual cases of SB mortality and amputations ranged from 24 (95% Confidence Interval: 19-29) and 28 (17-48) respectively in Guinea-Bissau with the highest estimates of 1927 (1529-2333) and 2368 (1506-4043) respectively in Nigeria. We calculated that the annual DALYs associated with a SB death ranged from 1550 DALYs (95%CI: 1227-1873 DALYs) in Guinea Bissau to 124,484 DALYs (95%CI: 98,773-150,712 DALYs) in Nigeria. The annual DALYs associated with amputation for the two countries were 149 DALYs (95%CI: 91-256 DALYs) and 12,621 DALYs (95%CI: 8027-21,549 DALYs) respectively. The total burden of SBE was estimated at 319,874 DALYs (95% CI: 248,357-402,654 DALYs) in the 16 countries in WA. These estimates are similar, and in some instances even higher, than for other NTDs encountered in WA (e.g., Buruli ulcer, Echinococcosis, Intestinal Nematode Infections, Leishmaniasis, Onchocerchiasis, Trachoma and Trypanosomiasis) as reported in the Global Burden of Diseases 2010 (GBD). CONCLUSIONS:The public health burden of SBE in WA is very substantial and similar to other more widely recognized NTDs. Efforts and funding commensurate with its burden should be made available for the control of snakebite in the sub-region.

It is estimated that India has more deaths from rabies than any other country. However, existing estimates are indirect and rely on non-representative studies.We examined rabies deaths in the ongoing Million Death Study (MDS), a representative survey of over 122,000 deaths in India that uses enhanced types of verbal autopsy. We estimated the age-specific mortality rates of symptomatically identifiable furious rabies and its geographic and demographic distributions. A total of 140 deaths in our sample were caused by rabies, suggesting that in 2005 there were 12,700 (99% CI 10,000 to 15,500) symptomatically identifiable furious rabies deaths in India. Most rabies deaths were in males (62%), in rural areas (91%), and in children below the age of 15 years (50%). The overall rabies mortality rate was 1.1 deaths per 100,000 population (99%CI 0.9 to 1.4). One third of the national rabies deaths were found in Uttar Pradesh (4,300) and nearly three quarters (8,900) were in 7 central and south-eastern states: Chhattisgarh, Uttar Pradesh, Odisha, Andhra Pradesh, Bihar, Assam, and Madhya Pradesh.Rabies remains an avoidable cause of death in India. As verbal autopsy is not likely to identify atypical or paralytic forms of rabies, our figure of 12,700 deaths due to classic and clinically identifiable furious rabies underestimates the total number of deaths due to this virus. The concentrated geographic distribution of rabies in India suggests that a significant reduction in the number of deaths or potentially even elimination of rabies deaths is possible.

India has long been thought to have more snakebites than any other country. However, inadequate hospital-based reporting has resulted in estimates of total annual snakebite mortality ranging widely from about 1,300 to 50,000. We calculated direct estimates of snakebite mortality from a national mortality survey.We conducted a nationally representative study of 123,000 deaths from 6,671 randomly selected areas in 2001-03. Full-time, non-medical field workers interviewed living respondents about all deaths. The underlying causes were independently coded by two of 130 trained physicians. Discrepancies were resolved by anonymous reconciliation or, failing that, by adjudication. A total of 562 deaths (0.47% of total deaths) were assigned to snakebites. Snakebite deaths occurred mostly in rural areas (97%), were more common in males (59%) than females (41%), and peaked at ages 15-29 years (25%) and during the monsoon months of June to September. This proportion represents about 45,900 annual snakebite deaths nationally (99% CI 40,900 to 50,900) or an annual age-standardised rate of 4.1/100,000 (99% CI 3.6-4.5), with higher rates in rural areas (5.4/100,000; 99% CI 4.8-6.0), and with the highest state rate in Andhra Pradesh (6.2). Annual snakebite deaths were greatest in the states of Uttar Pradesh (8,700), Andhra Pradesh (5,200), and Bihar (4,500).Snakebite remains an underestimated cause of accidental death in modern India. Because a large proportion of global totals of snakebites arise from India, global snakebite totals might also be underestimated. Community education, appropriate training of medical staff and better distribution of antivenom, especially to the 13 states with the highest prevalence, could reduce snakebite deaths in India.

Allergen immunotherapy presents an opportunity to define mechanisms of induction of clinical tolerance in humans. Significant progress has been made in our understanding of changes in T cell responses during immunotherapy, but existing work has largely been based on functional T cell assays. HLA-peptide-tetrameric complexes allow the tracking of antigen-specific T-cell populations based on the presence of specific T-cell receptors and when combined with functional assays allow a closer assessment of the potential roles of T-cell anergy and clonotype evolution. We sought to develop tools to facilitate tracking of antigen-specific T-cell populations during wasp-venom immunotherapy in people with wasp-venom allergy. We first defined dominant immunogenic regions within Ves v 5, a constituent of wasp venom that is known to represent a target antigen for T-cells. We next identified HLA-DRB1*1501 restricted epitopes and used HLA class II tetrameric complexes alongside cytokine responses to Ves v 5 to track T-cell responses during immunotherapy. In contrast to previous reports, we show that there was a significant initial induction of IL-4 producing antigen-specific T-cells within the first 3-5 weeks of immunotherapy which was followed by reduction of circulating effector antigen-specific T-cells despite escalation of wasp-venom dosage. However, there was sustained induction of IL-10-producing and FOXP3 positive antigen-specific T cells. We observed that these IL-10 producing cells could share a common precursor with IL-4-producing T cells specific for the same epitope. Clinical tolerance induction in humans is associated with dynamic changes in frequencies of antigen-specific T-cells, with a marked loss of IL-4-producing T-cells and the acquisition of IL-10-producing and FOXP3-positive antigen-specific CD4+ T-cells that can derive from a common shared precursor to pre-treatment effector T-cells. The development of new approaches to track antigen specific T-cell responses during immunotherapy can provide novel insights into mechanisms of tolerance induction in humans and identify new potential treatment targets.

BACKGROUND: In West Africa, envenoming by saw-scaled or carpet vipers (Echis ocellatus) causes great morbidity and mortality, but there is a crisis in supply of effective and affordable antivenom (ISRCTN01257358). METHODS: In a randomised, double-blind, controlled, non-inferiority trial, "EchiTAb Plus-ICP" (ET-Plus) equine antivenom made by Instituto Clodomiro Picado was compared to "EchiTAb G" (ET-G) ovine antivenom made by MicroPharm, which is the standard of care in Nigeria and was developed from the original EchiTAb-Fab introduced in 1998. Both are caprylic acid purified whole IgG antivenoms. ET-G is monospecific for Echis ocellatus antivenom (initial dose 1 vial) and ET-Plus is polyspecific for E. ocellatus, Naja nigricollis and Bitis arietans (initial dose 3 vials). Both had been screened by pre-clinical and preliminary clinical dose-finding and safety studies. Patients who presented with incoagulable blood, indicative of systemic envenoming by E. ocellatus, were recruited in Kaltungo, north-eastern Nigeria. Those eligible and consenting were randomly allocated with equal probability to receive ET-Plus or ET-G. The primary outcome was permanent restoration of blood coagulability 6 hours after the start of treatment, assessed by a simple whole blood clotting test repeated 6, 12, 18, 24 and 48 hr after treatment. Secondary (safety) outcomes were the incidences of anaphylactic, pyrogenic and late serum sickness-type antivenom reactions. FINDINGS: Initial doses permanently restored blood coagulability at 6 hours in 161/194 (83.0%) of ET-Plus and 156/206 (75.7%) of ET-G treated patients (Relative Risk [RR] 1.10 one-sided 95% CI lower limit 1.01; P = 0.05). ET-Plus caused early reactions on more occasions than did ET-G [50/194 (25.8%) and 39/206 (18.9%) respectively RR (1.36 one-sided 95% CI 1.86 upper limit; P = 0.06). These reactions were classified as severe in 21 (10.8%) and 11 (5.3%) of patients, respectively. CONCLUSION: At these doses, ET-Plus was slightly more effective but ET-G was slightly safer. Both are recommended for treating E. ocellatus envenoming in Nigeria. TRIAL REGISTRATION: Current Controlled Trials ISRCTN01257358.

The need for economical rabies post-exposure prophylaxis (PEP) is increasing in developing countries. Implementation of the two currently approved economical intradermal (ID) vaccine regimens is restricted due to confusion over different vaccines, regimens and dosages, lack of confidence in intradermal technique, and pharmaceutical regulations. We therefore compared a simplified 4-site economical PEP regimen with standard methods.Two hundred and fifty-four volunteers were randomly allocated to a single blind controlled trial. Each received purified vero cell rabies vaccine by one of four PEP regimens: the currently accepted 2-site ID; the 8-site regimen using 0.05 ml per ID site; a new 4-site ID regimen (on day 0, approximately 0.1 ml at 4 ID sites, using the whole 0.5 ml ampoule of vaccine; on day 7, 0.1 ml ID at 2 sites and at one site on days 28 and 90); or the standard 5-dose intramuscular regimen. All ID regimens required the same total amount of vaccine, 60% less than the intramuscular method. Neutralising antibody responses were measured five times over a year in 229 people, for whom complete data were available.All ID regimens showed similar immunogenicity. The intramuscular regimen gave the lowest geometric mean antibody titres. Using the rapid fluorescent focus inhibition test, some sera had unexpectedly high antibody levels that were not attributable to previous vaccination. The results were confirmed using the fluorescent antibody virus neutralisation method.This 4-site PEP regimen proved as immunogenic as current regimens, and has the advantages of requiring fewer clinic visits, being more practicable, and having a wider margin of safety, especially in inexperienced hands, than the 2-site regimen. It is more convenient than the 8-site method, and can be used economically with vaccines formulated in 1.0 or 0.5 ml ampoules. The 4-site regimen now meets all requirements of immunogenicity for PEP and can be introduced without further studies.Controlled-Trials.com ISRCTN 30087513.

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.