Publications by authors named "David A Warrell"

84 Publications

Epidemiology of snakebites in Kuwait.

Trans R Soc Trop Med Hyg 2021 May 15. Epub 2021 May 15.

Department of Biology, Jordan University of Science and Technology, Irbid, Jordan.

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.
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http://dx.doi.org/10.1093/trstmh/trab077DOI Listing
May 2021

Moderate-to-severe envenoming requiring ViperaTAb antivenom therapy in the UK.

Clin Toxicol (Phila) 2021 Mar 15:1-10. Epub 2021 Mar 15.

National Poisons Information Service - Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, UK.

Background: Bites by the European adder () 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 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.

Methods: 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 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.

Results: 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 ( = 19, 11.2%) or received antivenom more than 12 h after presenting to hospital ( = 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).

Conclusion: 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.
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http://dx.doi.org/10.1080/15563650.2021.1891245DOI Listing
March 2021

Scorpions and scorpion sting envenoming (scorpionism) in the Arab Countries of the Middle East.

Toxicon 2021 Feb 31;191:83-103. Epub 2020 Dec 31.

Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.

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 (Na) 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.
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http://dx.doi.org/10.1016/j.toxicon.2020.12.017DOI Listing
February 2021

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.

PLoS Negl Trop Dis 2020 11 16;14(11):e0008109. Epub 2020 Nov 16.

Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.

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.
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http://dx.doi.org/10.1371/journal.pntd.0008109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704047PMC
November 2020

Clinical importance of the Mandalay spitting cobra (Naja mandalayensis) in Upper Myanmar - Bites, envenoming and ophthalmia.

Toxicon 2020 Sep 3;184:39-47. Epub 2020 Jun 3.

Nuffield Department of Clinical Medicine, University of Oxford, UK. Electronic address:

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.
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http://dx.doi.org/10.1016/j.toxicon.2020.05.023DOI Listing
September 2020

Venoms, poisons and toxins: evolution and impact of amazing molecules.

J Venom Res 2020 12;10:1-6. Epub 2020 Jan 12.

Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007970PMC
January 2020

Terrestrial venomous snakes and snakebites in the Arab countries of the Middle East.

Toxicon 2020 Apr 27;177:1-15. Epub 2020 Jan 27.

Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.

The 12 Arab countries of the Middle East are inhabited by 21 species of terrestrial venomous snakes of varying medical importance. This review considers these species, consisting of 16 viperids, 3 elapids and 2 atractaspidines. Iraq, Jordan, Lebanon, Oman, Saudi Arabia, and Yemen report the largest numbers of snakebites and envenomings. Accessible literature in English and Arabic on venomous snakes and snakebites and available antivenoms is reviewed. Clinical effects include potentially misleading symptoms attributable to anxiety and traditional pre-hospital treatments.
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http://dx.doi.org/10.1016/j.toxicon.2020.01.012DOI Listing
April 2020

Novel long-chain neurotoxins from distinguish the two binding sites in muscle-type nicotinic acetylcholine receptors.

Biochem J 2019 04 26;476(8):1285-1302. Epub 2019 Apr 26.

Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia.

αδ-Bungarotoxins, a novel group of long-chain α-neurotoxins, manifest different affinity to two agonist/competitive antagonist binding sites of muscle-type nicotinic acetylcholine receptors (nAChRs), being more active at the interface of α-δ subunits. Three isoforms (αδ-BgTx-1-3) were identified in Malayan Krait () from Thailand by genomic DNA analysis; two of them (αδ-BgTx-1 and 2) were isolated from its venom. The toxins comprise 73 amino acid residues and 5 disulfide bridges, being homologous to α-bungarotoxin (α-BgTx), a classical blocker of muscle-type and neuronal α7, α8, and α9α10 nAChRs. The toxicity of αδ-BgTx-1 (LD = 0.17-0.28 µg/g mouse, i.p. injection) is essentially as high as that of α-BgTx. In the chick biventer cervicis nerve-muscle preparation, αδ-BgTx-1 completely abolished acetylcholine response, but in contrast with the block by α-BgTx, acetylcholine response was fully reversible by washing. αδ-BgTxs, similar to α-BgTx, bind with high affinity to α7 and muscle-type nAChRs. However, the major difference of αδ-BgTxs from α-BgTx and other naturally occurring α-neurotoxins is that αδ-BgTxs discriminate the two binding sites in the and mouse muscle nAChRs showing up to two orders of magnitude higher affinity for the α-δ site as compared with α-ε or α-γ binding site interfaces. Molecular modeling and analysis of the literature provided possible explanations for these differences in binding mode; one of the probable reasons being the lower content of positively charged residues in αδ-BgTxs. Thus, αδ-BgTxs are new tools for studies on nAChRs.
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http://dx.doi.org/10.1042/BCJ20180909DOI Listing
April 2019

Louse-borne relapsing fever (Borrelia recurrentis infection).

Authors:
David A Warrell

Epidemiol Infect 2019 01;147:e106

Nuffield Department of Clinical Medicine,University of Oxford,Oxford,UK.

Louse-borne relapsing fever (LBRF) is an epidemic disease with a fascinating history from Hippocrates' times, through the 6th century 'Yellow Plague', to epidemics in Ireland, Scotland and England in the 19th century and two large Afro-Middle Eastern pandemics in the 20th century. An endemic focus persists in Ethiopia and adjacent territories in the Horn of Africa. Since 2015, awareness of LBRF in Europe, as a re-emerging disease, has been increased dramatically by the discovery of this infection in dozens of refugees arriving from Africa.The causative spirochaete, Borrelia recurrentis, has a genome so similar to B. duttonii and B. crocidurae (causes of East and West African tick-borne relapsing fever), that they are now regarded as merely ecotypes of a single genomospecies. Transmission is confined to the human body louse Pediculus humanus corporis, and, perhaps, the head louse P. humanus capitis, although the latter has not been proved. Infection is by inoculation of louse coelomic fluid or faeces by scratching. Nosocomial infections are possible from contamination by infected blood. Between blood meals, body lice live in clothing until the host's body temperature rises or falls, when they seek a new abode.The most distinctive feature of LBRF, the relapse phenomenon, is attributable to antigenic variation of borrelial outer-membrane lipoprotein. High fever, rigors, headache, pain and prostration start abruptly, 2-18 days after infection. Petechial rash, epistaxis, jaundice, hepatosplenomegaly and liver dysfunction are common. Severe features include hyperpyrexia, shock, myocarditis causing acute pulmonary oedema, acute respiratory distress syndrome, cerebral or gastrointestinal bleeding, ruptured spleen, hepatic failure, Jarisch-Herxheimer reactions (J-HR) and opportunistic typhoid or other complicating bacterial infections. Pregnant women are at high risk of aborting and perinatal mortality is high.Rapid diagnosis is by microscopy of blood films, but polymerase chain reaction is used increasingly for species diagnosis. Severe falciparum malaria and leptospirosis are urgent differential diagnoses in residents and travellers from appropriate geographical regions.High untreated case-fatality, exceeding 40% in some historic epidemics, can be reduced to less than 5% by antibiotic treatment, but elimination of spirochaetaemia is often accompanied by a severe J-HR.Epidemics are controlled by sterilising clothing to eliminate lice, using pediculicides and by improving personal hygiene.
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http://dx.doi.org/10.1017/S0950268819000116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518520PMC
January 2019

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

PLoS Negl Trop Dis 2019 02 15;13(2):e0007171. Epub 2019 Feb 15.

Department of Renal Medicine, Royal Adelaide Hospital, Adelaide, Australia.

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.
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http://dx.doi.org/10.1371/journal.pntd.0007171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395000PMC
February 2019

Venomous Bites, Stings, and Poisoning: An Update.

Authors:
David A Warrell

Infect Dis Clin North Am 2019 03;33(1):17-38

Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK. Electronic address:

This article discusses the epidemiology, prevention, clinical features, and treatment of venomous bites by snakes, lizards, and spiders; stings by fish, jellyfish, echinoderms, insects, and scorpions; and poisoning by ingestion of fish, turtles, and shellfish. Invertebrate stings cause fatalities by anaphylaxis, secondary to acquired hypersensitivity (Hymenoptera, such as bees, wasps, and ants; and jellyfish), and by direct envenoming (scorpions, spiders, jellyfish, and echinoderms). Simple preventive techniques, such as wearing protective clothing, using a flashlight at night, and excluding venomous animals from sleeping quarters, are of paramount importance to reduce the risk of venomous bites and stings.
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http://dx.doi.org/10.1016/j.idc.2018.10.001DOI Listing
March 2019

The Imperative of Palliation in the Management of Rabies Encephalomyelitis.

Trop Med Infect Dis 2017 Oct 4;2(4). Epub 2017 Oct 4.

Institut Pasteur de Nouvelle-Calédonie, BP 61 ⁻ 98845 Nouméa cedex, New Caledonia.

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.
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http://dx.doi.org/10.3390/tropicalmed2040052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6082067PMC
October 2017

Development of an ELISA assay to determine neutralising capacity of horse serum following immunisation with Daboia siamensis venom in Myanmar.

Toxicon 2018 Sep 11;151:163-168. Epub 2018 Jul 11.

Royal Adelaide Hospital, South Australia, Australia; University of Adelaide, South Australia, Australia. Electronic address:

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.
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http://dx.doi.org/10.1016/j.toxicon.2018.07.012DOI Listing
September 2018

Vulnerability to snakebite envenoming: a global mapping of hotspots.

Lancet 2018 08 17;392(10148):673-684. Epub 2018 Jul 17.

Institute for Health Metrics and Evaluation, University of Washington, Seattle, WA, USA.

Background: Snakebite envenoming is a frequently overlooked cause of mortality and morbidity. Data for snake ecology and existing snakebite interventions are scarce, limiting accurate burden estimation initiatives. Low global awareness stunts new interventions, adequate health resources, and available health care. Therefore, we aimed to synthesise currently available data to identify the most vulnerable populations at risk of snakebite, and where additional data to manage this global problem are needed.

Methods: We assembled a list of snake species using WHO guidelines. Where relevant, we obtained expert opinion range (EOR) maps from WHO or the Clinical Toxinology Resources. We also obtained occurrence data for each snake species from a variety of websites, such as VertNet and iNaturalist, using the spocc R package (version 0.7.0). We removed duplicate occurrence data and categorised snakes into three groups: group A (no available EOR map or species occurrence records), group B (EOR map but <5 species occurrence records), and group C (EOR map and ≥5 species occurrence records). For group C species, we did a multivariate environmental similarity analysis using the 2008 WHO EOR maps and newly available evidence. Using these data and the EOR maps, we produced contemporary range maps for medically important venomous snake species at a 5 × 5 km resolution. We subsequently triangulated these data with three health system metrics (antivenom availability, accessibility to urban centres, and the Healthcare Access and Quality [HAQ] Index) to identify the populations most vulnerable to snakebite morbidity and mortality.

Findings: We provide a map showing the ranges of 278 snake species globally. Although about 6·85 billion people worldwide live within range of areas inhabited by snakes, about 146·70 million live within remote areas lacking quality health-care provisioning. Comparing opposite ends of the HAQ Index, 272·91 million individuals (65·25%) of the population within the lowest decile are at risk of exposure to any snake for which no effective therapy exists compared with 519·46 million individuals (27·79%) within the highest HAQ Index decile, showing a disproportionate coverage in reported antivenom availability. Antivenoms were available for 119 (43%) of 278 snake species evaluated by WHO, while globally 750·19 million (10·95%) of those living within snake ranges live more than 1 h from population centres. In total, we identify about 92·66 million people living within these vulnerable geographies, including many sub-Saharan countries, Indonesia, and other parts of southeast Asia.

Interpretation: Identifying exact populations vulnerable to the most severe outcomes of snakebite envenoming at a subnational level is important for prioritising new data collection and collation, reinforcing envenoming treatment, existing health-care systems, and deploying currently available and future interventions. These maps can guide future research efforts on snakebite envenoming from both ecological and public health perspectives and better target future estimates of the burden of this neglected tropical disease.

Funding: Bill & Melinda Gates Foundation.
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http://dx.doi.org/10.1016/S0140-6736(18)31224-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115328PMC
August 2018

Clinical studies of the effectiveness and safety of antivenoms.

Toxicon 2018 Aug 7;150:1-10. Epub 2018 May 7.

Australian Venom Research Unit, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, VIC, 3010, Australia; Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 9DU, UK. Electronic address:

In the 1890s, hyperimmune sera proved effective in animals against challenge by the snake venom against which they had been raised. They were first used, apparently successfully, in a human patient in about 1895. Since then, antivenoms have become accepted as the only reliable specific treatment for snake-bite envenoming. Despite decades of accumulated clinical experience and a number of published randomized comparative and observational studies, the clinical effectiveness and safety of some antivenoms remain open to question, due to a lack of robust randomized controlled trial data. Antivenoms in some poorly regulated markets may have high rates of potentially fatal adverse effects and their use must be balanced by demonstrable effectiveness. Even those manufactured to strict regulatory requirements may pose a rare risk of severe adverse reactions. Most antivenoms currently marketed around the world were registered without first being studied clinically. There is increasing pressure to subject antivenoms, even those that are long-established, to the same protocols of rigorous pre-clinical and clinical assessment that are standard regulatory requirements for other drugs. Conventional clinical testing progresses through Phases I, II, III to IV. Most authorities consider antivenoms too dangerous to be used in Phase I studies in healthy volunteers. An alternative method for preliminary estimation of safety, dose-finding and effectiveness, is proposed - the "3 + 3" dose escalation or de-escalation design, in volunteer patients, as used in oncology to test cytotoxic drugs. Antivenoms are so widely used and well trusted, that there are few ethical justifications for placebo controls. However, placebo might be ethically justified if there were no proven effective treatment and or if withholding or delaying treatment posed acceptably negligible risks to the participants. Antivenom trials are most urgently needed in low-to middle-income countries where there are many practical, logistical and funding challenges. Basic requirements for clinical trials include identification of the biting species of snake in every case; the use of objective, clinically-relevant endpoints, such as restoration of blood coagulability; definition of inclusion, exclusion and withdrawal criteria; assurance of antivenom safety; ethical considerations; inclusion of one or more control (comparator) groups; and analysis based on intention to treat. The highest quality evidence comes from Phase II and larger Phase III studies that have been designed as statistically powerful, randomized, controlled trials (RCTs), ideally with blinding of patients and investigators to avoid bias. Because of the challenges to carrying out clinical trials of antivenoms, Phase IV trials (post-marketing surveillance) are potentially more important and useful than for most other drugs.
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http://dx.doi.org/10.1016/j.toxicon.2018.05.001DOI Listing
August 2018

Snakebite envenoming.

Nat Rev Dis Primers 2017 10 5;3:17079. Epub 2017 Oct 5.

This corrects the article DOI: 10.1038/nrdp.2017.63.
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http://dx.doi.org/10.1038/nrdp.2017.79DOI Listing
October 2017

Snakebite envenoming.

Nat Rev Dis Primers 2017 Sep 14;3:17063. Epub 2017 Sep 14.

Nuffield Department of Clinical Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK.

Snakebite envenoming is a neglected tropical disease that kills >100,000 people and maims >400,000 people every year. Impoverished populations living in the rural tropics are particularly vulnerable; snakebite envenoming perpetuates the cycle of poverty. Snake venoms are complex mixtures of proteins that exert a wide range of toxic actions. The high variability in snake venom composition is responsible for the various clinical manifestations in envenomings, ranging from local tissue damage to potentially life-threatening systemic effects. Intravenous administration of antivenom is the only specific treatment to counteract envenoming. Analgesics, ventilator support, fluid therapy, haemodialysis and antibiotic therapy are also used. Novel therapeutic alternatives based on recombinant antibody technologies and new toxin inhibitors are being explored. Confronting snakebite envenoming at a global level demands the implementation of an integrated intervention strategy involving the WHO, the research community, antivenom manufacturers, regulatory agencies, national and regional health authorities, professional health organizations, international funding agencies, advocacy groups and civil society institutions.
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http://dx.doi.org/10.1038/nrdp.2017.63DOI Listing
September 2017

Snakebites: reducing their international impact.

Authors:
David A Warrell

Med J Aust 2017 08;207(3):112-113

University of Oxford, Oxford, United Kingdom

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http://dx.doi.org/10.5694/mja17.00480DOI Listing
August 2017

Individual variability of venom from the European adder (Vipera berus berus) from one locality in Eastern Hungary.

Toxicon 2017 Sep 9;135:59-70. Epub 2017 Jun 9.

University of Debrecen, Department of Botany, Faculty of Science and Technology, Egyetem tér 1, H-4010, Debrecen, Hungary; CETOX - Analytical and Toxicological Research and Consultant Ltd., Egyetem tér 1, H-4032, Debrecen, Hungary.

We have revealed intra-population variability among venom samples from several individual European adders (Vipera berus berus) within a defined population in Eastern Hungary. Individual differences in venom pattern were noticed, both gender-specific and age-related, by one-dimensional electrophoresis. Gelatin zymography demonstrated that these individual venoms have different degradation profiles indicating varying protease activity in the specimens from adders of different ages and genders. Some specimens shared a conserved region of substrate degradation, while others had lower or extremely low protease activity. Phospholipase A activity of venoms was similar but not identical. Interspecimen diversity of the venom phospholipase A-spectra (based on the components' molecular masses) was detected by MALDI-TOF MS. The lethal toxicity of venoms (LD) also showed differences among individual snakes. Extracted venom samples had varying neuromuscular paralysing effect on chick biventer cervicis nerve-muscle preparations. The paralysing effect of venom was lost when calcium in the physiological salt solution was replaced by strontium; indicating that the block of twitch responses to nerve stimulation is associated with the activity of a phospholipase-dependent neurotoxin. In contrast to the studied V. b. berus venoms from different geographical regions so far, this is the first V. b. berus population discovered to have predominantly neurotoxic neuromuscular activity. The relevance of varying venom yields is also discussed. This study demonstrates that individual venom variation among V. b. berus living in particular area of Eastern Hungary might contribute to a wider range of clinical manifestations of V. b. berus envenoming than elsewhere in Europe.
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http://dx.doi.org/10.1016/j.toxicon.2017.06.004DOI Listing
September 2017

Cost-Effectiveness of Antivenoms for Snakebite Envenoming in 16 Countries in West Africa.

PLoS Negl Trop Dis 2016 Mar 30;10(3):e0004568. Epub 2016 Mar 30.

College of Health of Sciences, Bayero University, Kano, Nigeria.

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.
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http://dx.doi.org/10.1371/journal.pntd.0004568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4814077PMC
March 2016

Snakebite is Under Appreciated: Appraisal of Burden from West Africa.

PLoS Negl Trop Dis 2015 Sep 23;9(9):e0004088. Epub 2015 Sep 23.

Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.

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.
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http://dx.doi.org/10.1371/journal.pntd.0004088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4580425PMC
September 2015

A Call for Incorporating Social Research in the Global Struggle against Snakebite.

PLoS Negl Trop Dis 2015 Sep 17;9(9):e0003960. Epub 2015 Sep 17.

Australian Venom Research Unit, Department of Pharmacology & Therapeutics, University of Melbourne, Parkville, Victoria, Australia; Charles Campbell Toxinology Centre, School of Medicine & Health Sciences, University of Papua New Guinea, Port Moresby, Papua New Guinea.

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http://dx.doi.org/10.1371/journal.pntd.0003960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4574917PMC
September 2015

Rabies: the clinical features, management and prevention of the classic zoonosis.

Clin Med (Lond) 2015 Feb;15(1):78-81

Royal College of Physicians, London, UK, and emeritus professor of tropical medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.

The diagnosis of rabies encephalitis relies on awareness of the varied clinical features and eliciting a history of unusual contact with a mammal throughout the endemic area. The diagnosis is easily missed. Laboratory tests are not routine and only confirm clinical suspicion. Rabies infection carries a case fatality exceeding 99.9%. Palliation is appropriate, except for previously-vaccinated patients or those infected by American bats, for whom intensive care is probably indicated. However, as rabies vaccines are outstandingly effective, no one should die of dog-transmitted infection. Vaccines and rabies immunoglobulin are expensive and usually scarce in Asia and Africa. All travellers to dog rabies enzootic areas should be strongly encouraged to have pre-exposure immunisation before departure. There is no contraindication to vaccination but the cost can be prohibitive. Intradermal immunisation, using 0.1 ml and sharing vials of vaccine, is cheaper and is now permitted by UK regulations. Returning travellers may need post-exposure prophylaxis. Economical intradermal post-exposure vaccination is practicable and should be introduced into rural areas of Africa and Asia immediately. Eliminating rabies in dogs is now feasible and would dramatically reduce human mortality, if funds were made available. The high current economic burden of human prophylaxis would then be largely relieved.
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http://dx.doi.org/10.7861/clinmedicine.14-6-78DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4954532PMC
February 2015

A multicomponent strategy to improve the availability of antivenom for treating snakebite envenoming.

Bull World Health Organ 2014 Jul 4;92(7):526-32. Epub 2014 Mar 4.

Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Australia .

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.
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http://dx.doi.org/10.2471/BLT.13.132431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4121869PMC
July 2014

New approaches & technologies of venomics to meet the challenge of human envenoming by snakebites in India.

Indian J Med Res 2013 ;138:38-59

Global Snakebite Initiative, P.O. Box 193, Herston, Qld, 4029, Australia; Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK, .

The direct estimate of 46,000 snakebite deaths in India in 2005 (1 for every 2 HIV/AIDS deaths), based on verbal autopsies, renders unrealistic the total of only 47,000 snakebite deaths in the whole world in 2010, obtained indirectly as part of the "Global Burden of Disease 2010" study. Persistent underestimation of its true morbidity and mortality has made snakebite the most neglected of all the WHO's "neglected tropical diseases", downgrading its public health importance. Strategies to address this neglect should include the improvement of antivenom, the only specific antidote to envenoming. To accommodate increased understanding of geographical intraspecific variation in venom composition and the range of snake species that are medically important in India, the design of antivenoms (choice of venom sources and species coverage) should be reconsidered. Methods of preclinical and clinical testing should be improved. The relatively new science of venomics involves techniques and strategies for assessing the toxin composition of snake venoms directly through proteomics-centred approaches or indirectly via high-throughput venom gland transcriptomics and bioinformatic analysis. Antivenomics is translational venomics: a proteomics-based protocol to quantify the extent of cross-reactivity of antivenoms against homologous and heterologous venoms. These approaches could revolutionize the preclinical assessment of antivenom efficacy, leading to a new generation of antivenoms that are clinically more effective.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3767246PMC
April 2014

Non-front-fanged colubroid snakes: a current evidence-based analysis of medical significance.

Toxicon 2013 Jul 24;69:103-13. Epub 2013 Feb 24.

Department of Toxinology, Women's and Children's Hospital, 72 King William St., North Adelaide, South Australia, Australia.

Non-front-fanged colubroid snakes (NFFC; formerly and artificially taxonomically assembled as "colubrids") comprise about 70% of extant snake species and include several taxa now known to cause lethal or life threatening envenoming in humans. Although the medical risks of bites by only a handful of species have been documented, a growing number of NFFC are implicated in medically significant bites. The majority of these snakes have oral products (Duvernoy's secretions, or venoms) with unknown biomedical properties and their potential for causing harm in humans is unknown. Increasingly, multiple NFFC species are entering the commercial snake trade posing an uncertain risk. Published case reports describing NFFC bites were assessed for evidence-based value, clinical detail and verified species identification. These data were subjected to meta-analysis and a hazard index was generated for select taxa. Cases on which we consulted or personally treated were included and subjected to the same assessment criteria. Cases involving approximately 120 species met the selection criteria, and a small subset designated Hazard Level 1 (most hazardous), contained 5 species with lethal potential. Recommended management of these cases included antivenom for 3 species, Dispholidus typus, Rhabdophis tiginis, Rhabdophis subminiatus, whereas others in this subset without commercially available antivenoms (Thelotornis spp.) were treated with plasma/erythrocyte replacement therapy and supportive care. Heparin, antifibrinolytics and/or plasmapheresis/exchange transfusion have been used in the management of some Hazard Level 1 envenomings, but evidence-based analysis positively contraindicates the use of any of these interventions. Hazard Level 2/3 species were involved in cases containing mixed quality data that implicated these taxa (e.g. Boiga irregularis, Philodryas olfersii, Malpolon monspessulanus) with bites that caused rare systemic effects. Recommended management may include use of acetylcholinesterase inhibitors (e.g. neostigmine) and wound care on a case-by-case basis. Hazard level 3 species comprised a larger group capable of producing significant local effects only, often associated with a protracted bite (eg Heterodon nasicus, Borikenophis (Alsophis) portoricensis, Platyceps (Coluber) rhodorachis). Management is restricted to wound care. Bites by Hazard level 4 species comprised the majority of surveyed taxa and these showed only minor effects of no clinical importance. This study has produced a comprehensive evidence-based listing of NFFC snakes tabulated against medical significance of bites, together with best-practice management recommendations. This analysis assumes increasing importance, as there is growing exposure to lesser-known NFFC snakes, particularly in captive collections that may uncover further species of significance in the future. Careful and accurate documentation of bites by verified species of NFFC snakes is required to increase the evidence base and establish the best medical management approach for each species.
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http://dx.doi.org/10.1016/j.toxicon.2013.02.003DOI Listing
July 2013

Antivenom therapy of carpet viper (Echis ocellatus) envenoming: effectiveness and strategies for delivery in West Africa.

Toxicon 2013 Jul 20;69:82-9. Epub 2013 Jan 20.

Infectious & Tropical Diseases Unit, Department of Medicine, Bayero University Kano, Aminu Kano Teaching Hospital, Kano, Kano State, Nigeria.

In West Africa, response to specific, geographically appropriate, antivenom is often dramatic following carpet viper (Echis ocellatus) envenoming with rapid restoration of blood coagulability and resolution of spontaneous haemorrhage. Envenoming from Australasian snakes causing similar coagulopathies may respond less dramatically and the effectiveness of antivenom is being questioned. Here we have reviewed and re-analysed all published preclinical and clinical studies on envenoming and antivenom therapy conducted in West Africa to determine the effectiveness of antivenom. 22 studies provided relevant information: 12 observational studies, 4 RCTs and 6 preclinical studies. Four comparative studies confirmed statistically significant protection against mortality ranging from 57 to 87% using specific antivenoms compared to non-specific or no antivenoms. Meta-analysis estimated combined Odds Ratio (95% CI) of 0.25 (0.14-0.45) of dying among those treated with specific antivenom or 75% (95% CI: 55-86%) protection against death. Mortality more than doubled during times when stocks of reliable antivenoms ran out, with Relative Risk (95% CI)] of 2.33 (1.26-4.06). Serum kinetics of venom antigen/antivenom levels also confirmed that decline of venom antigen levels coincided with resolution of coagulopathy while decline of antivenom levels was associated with venom antigen reappearance and recurrence of coagulopathy. Preclinical and antivenomics analysis confirmed efficacy of regionally appropriate antivenoms against E. ocellatus and related species' venoms in Sub-Saharan Africa but not against Asian Echis carinatus venom. Antivenoms raised against E. carinatus were ineffective in human studies. In West Africa, specific antivenom is effective in managing carpet viper envenoming. A centralized hub-and-spoke strategy is suggested for broadening antivenom access to endemic rural areas together with instituting quality assurance, standardization and manpower training. Benefits, risks, cost-effectiveness and feasibility of the approach should be formally assessed.
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http://dx.doi.org/10.1016/j.toxicon.2013.01.002DOI Listing
July 2013