Reviews by David A. Warrell

1. Envenoming and poisoning by animals: the most neglected of all human diseases (Review of the first www-based version of the VAPAGuide, 2011, by David A. Warrell)

During a career largely devoted to research on neglected tropical diseases, I have encountered the greatest difficulty in persuading scientific colleagues, fellow physicians, international organisations such as the World Health Organization and funding bodies, of the importance and unmet challenge presented by envenoming and poisoning by animals. To admit an interest in this subject has sometimes provoked facetious remarks and inappropriate humour.In some circles I have been branded as merely an entertainer or as a purveyor of esoteric diseases, perhaps colourful and exotic, but scarcely a worthy subject for academic endeavour. However, the accumulation of sound epidemiological data over the past few decades has begun to quantify the burden of human suffering attributable to conditions such as snake bite, scorpion stings, hymenoptera sting allergy and ciguatera fish poisoning. These diseases have proved to be important causes of morbidity and/or mortality in many tropical developing countries, targeting vulnerable and impoverished populations including young children. Even in Western countries that have a sparse toxifauna, envenoming by exotic animals kept (often illegally) as pets and poisoning from eating imported tropical reef fish, are an increasing challenge for inexperienced poisons centres and toxicologists.

I am unrepentant in my passion for these long-ignored diseases. In trying to understand the reasons for their neglect by medical science, one might speculate that an innate primordial fear of snakes and other venomous animals has led to denial or humorous dismissal of the public health problems that they cause.Other more obvious, better publicised and fashionable illnesses have been prioritised to the detriment of support for animal toxin diseases. Below are some examples that should prompt their urgent reconsideration and reprioritisation.

Snake bites in South Asia

Any claim that a disease is unjustly neglected must be built on reliable quantitative evidence that it causes substantial mortality or morbidity. Until recently, community-based data (independent of the notorious underreporting inherent in hospital returns) were available for only a few focal areas of Africa and Asia. For many years, estimates of the burden of snake bite nationally and globally have been calculated by extrapolations within and between countries, resulting in outrageous inaccuracies. However, direct national estimates based on well designed community surveys have now been published. They show annual snake bite mortalities of approximately6,000 in Bangladesh (Rahman et al. 2010) and 45,900 (95% CI 40,900–50,900) in India (Mohapatra et al. 2011). The figure for Indiais 30-foldhigher than has been declared in official hospital returns published on the Government of India’s web-site (Government of India, Central Bureau of Health Intelligence 2008).

Scorpion stings

Frequent scorpion stings with fatalities especially in children have been reported from North and South Africa, The Middle East, North-Western India, Mexico and South America. A recent review suggested an annual global incidence of more than 1.2 million stings causing more than 3, 250 fatalities (case fatality 0.27%) (Chippaux and Goyffon 2008).

Hymenoptera sting anaphylaxis

Acquired Type 1, IgE-mediated hypersensitivity to the venoms of Hymenoptera (bees, wasps, yellow jackets, hornets, ants) is a common public health problem in most parts of the world. In many countries, stings by Hymenoptera are the commonest cause of anaphylaxis in adults. The incidence of systemic reactions to stings is estimated to be 0.8–5 %, and of severe local reactions 19 %, while the prevalence of hypersensitisation, indicated by the presence of venom specific IgE, detected by skin tests or RAST, may be as high as 25 % of the population. Deaths from Hymenoptera sting anaphylaxis are often unsuspected, undetected and consequently underreported, but this condition kills at least 200 people each year in Europe alone (Müller 2010).

Ciguatera fish poisoning

Ciguatoxins derived from Gambierdiscus dinoflagellates and accumulated in tropical reef fish are the commonest cause of seafood poisoning in Pacific and Caribbean archipelagos, where more than 50% of island populations may be affected. Exposure to ciguatoxins has become globalised as a result of increasing appetites for exotic fish and demands by immigrant populations in Western countries. Endemic ciguatera poisoning has also extended its known geographical limits, to the Eastern Atlantic, Western Gulf of Mexico, Eastern Mediterranean and elsewhere. Estimates of the annual global incidence of ciguatera poisoning range from 25,000 to 500,000 (Dickey and Plakas 2010). Disease recognition is made difficult by the lack of widely available rapid diagnostic assays and ignorance of the distinctive clinical syndrome.

The need for better information and training in Clinical Toxinology

All these examples of the increasing perception of the burden of diseases attributable to animal venoms and poisons should encourage attempts to improve understanding, prevention and treatment - the realm of clinical toxinology. Free, online availability of Junghanss and Bodio’s new “VAPAGuide” will make an important contribution to this strategy. It is being launched at a very opportune moment, when there is increasing demand for up-to-date information on all aspects of clinical toxinology by a new generation of medical professionals which has largely abandoned consulting hard copy books and journals in libraries, in favour of rapidly accessible electronic resources.Built on the pioneering design, many original features and impressively broad database of the 1996 publication “Notfall-Handbuch Gifftiere”, the VAPAGuide will reach a much wider audience. The German word “Gift” does not distinguish between injected “venom” and ingested “poison”, but the language of Goethe, Schiller and Rilke is no less beautiful, powerful and expressive than the language of Milton, Shakespeare and Shelley. However, English is now much more widely understood, making it the appropriate vehicle for the VAPAGuide.

I welcome this new enterprise with great enthusiasm. It greatly expands the information that is readily available to toxinologists, toxicologists, poisons centre consultants, medical practitioners, zoologists and interested lay people, including explorers, travellers, tourists, wilderness enthusiasts and field workers. A challenge will be to keep it updated, abreast of emerging new information in a rapidly expanding field of medical science. I am confident that this is well within the proven capabilities of the VAPAGuide team.

David A. Warrell

Emeritus Professor of Tropical Medicine

University of Oxford, UK

May 2011

2. Introduction to the Handbook 'Notfallhandbuch Gifttiere'  by David A. Warrell (excerpt from Junghanss and Bodio, 1996)

Animal toxins fall into two main groups: venoms, substances secreted by specialised glands and actively injected or squirted on to skin or absorbent mucous membranes such as the conjunctivae; and poisons, which are licked or swallowed. The venom apparatus, evolved to
inject venom into the animal’s prey or enemies, takes many forms. Relatively crude methods of venom injection are used by some colubrid snakes, shrews and vampire bats which have solid ungrooved teeth, octopuses which have beaks, ticks which have hypostomes and leeches
which have jaws. Snakes, lizards and solenodons (venomous insectivorous mammal from Haiti and Cuba) have grooved or cannulated teeth termed fangs; spiders have venom jaws and centipedes have a pair of claws (forcipules) modified to sting; the male platypus has venom spurs; fish, sea urchins, insects and scorpions have rigid needle-like stings; cnidarians (coelentarates) have stinging hairs; sea urchins have venomous grapples (pedicellariae); while one of the most complex and astonishing forms of venom apparatus is the harpoon and radular tooth of the cone shells which are carnivorous marine snails. "Spitting" or squirting venom seems to be largely a defensive form of behaviour displayed by spitting cobras and rinkhals, toads, scorpions, harvestmen, whip scorpions, pseudoscorpions, blister beetles and millipedes.

Animal venoms are often complex mixtures of proteins and other compounds whose biological function is to immobilise relatively large and vigorous prey species, to digest this prey and, in some cases, for use in defence, fighting and, in the case of "blood-sucking" species such as vampire bats, ticks and leeches, to promote bleeding. Immobilisation of the prey is achieved by venom components which cause paralyses, unconsciousness and pathophysiological processes leading rapidly to death, such as massive intravascular coagulation, shock and even severe pain and fear. The degree of "overkill" achievable by a single venom can be amazing. In many cases venoms contain numerous different neurotoxins active against a variety of target receptors; several anti haemostatic components acting synergistically and biological activities directed against many organs and tissues. The biological function of animal poisons are not always as clear as those of venoms and in some cases the presence of a poison in the tissues of an animal may be merely the result of its acquisition through the food chain (for example dinoflagellate toxins in poisonous shellfish) or by infection (for example scombroid fish poisoning). However, the highly potent poisons secreted onto the moist integument of amphibians may protect these vulnerable respiratory organs against infection by micro-organisms. The possession
of a poisonous skin (eg dendrobatid frogs) or feathers (eg pitohuis), together with striking warning coloration, may provide individuals with a selective advantage; predators may spit them out alive or avoid them altogether. The best evidence of the protective value of being venomous or poisonous are various forms or mimicry of the colour, form or behaviour of these animals by nonvenomous species.

The exercise of evolutionary pressures over millions of years has resulted in an enormous diversity of mechanisms by which venoms interfere with physiological functions. As a result, venoms have proved powerful tools for investigating a variety of physiological functions including blood coagulation, neuromuscular transmission, central nervous system function, blood pressure control and the complement system. It is the possession of such diverse and potently damaging properties that create a medical emergency when a human is bitten, stung or poisoned. In trying to interpret the symptoms, signs and results of investigations in envenomed or poisoned patients, the clinical toxinologist must always bear in mind the essential inappropriateness of the human as a target for animal toxins intended for the much smaller prey species. However, even in doses which are inappropriately small in relation to body weight, many toxins can produce severe and life-threatening effects in the human victim. Ideally, these accidents should be prevented through knowledge of the preferred habitats and behaviour of venomous species, by wearing protective clothing and avoiding unnecessary exposure. Unfortunately, in most areas of the rural tropics where venomous bites
and stings are most common, local people are unable to avoid exposure.

Outside the tropics, pet owners, herpetologists, entomologists and aquarium specialists may be bitten or stung by exotic species usually on their hands. Damaging effects of envenoming can develop rapidly after injection or ingestion of animal toxins and so first aid treatment is of great potential benefit. Few methods are both effective and practicable, but the use of self-injectable adrenaline for hymenoptera venom anaphylaxis, hot water treatment for fish stings and pressure immobilisation for bites by neurotoxic elapid snakes have proved valuable. Identification of the animal responsible is extremely important, but the necessary skills are rarely taught in medical schools or nursing colleges. The ideal medical treatment for envenoming and poisoning would be neutralization of the toxin by a specific antidote. Antivenoms were first used therapeutically in animals und humans by Albert Calmette almost 100 years ago. The overriding importance of species specificity of antivenoms was quickly recognised during the 100 years in which they have been used. Their deploymnet and use, in adequate doses, early in the naturals history of envenoming, is constrained by cost, inadequate supplies and the high risk of anaphylactic reactions when they are given by the optimal intravenous route. The role of ancillary pharmacological agents has not been adequately explored. In many cases of severe envenoming, once specific antivenom has been given (if available), the patient’s survival will depend on supportive treatment in an intensive care unit. Overall, the correct diagnosis and optimal clinical management of a case of severe envenoming or poisoning may require the exercise of high levels of zoological and medical skills and some detective work. Therein lies the challenge and reward of this speciality of clinical toxinology.

Probably the oldest surviving treatise on snake bite and its treatment is contained in the Brooklyn Papyrus whose original may date from before 2000 BC. Cryptic and tantalizing in its allusions to long forgotten medical traditions and heavily laced with pharaonic mysticisms and deities, the papyrus describes medical and surgical treatments, some of which, such as onions and incisions, are used by traditional therapists to this day. Four millennia later, Thomas Junghanns and Mauro Bodio have produced a unique and scholarly compendium on venomous and poisonous animals. Never before has such a work been researched with greater care, more extensive travel or more consultation with local experts in each region of the world. Why is such a work necessary? In northern Europe, clinicians and poisons information services receive relatively few enquiries about animal toxins. However, most parts of the world, and especially tropical countries, possess a rich venomous and poisonous
fauna. In some areas the incidence of morbidity and mortality from snake bites and scorpion stings rivals that from road traffic accidents (> 10/100 000 population/year) and the case fatality is a high as bubonic plague (10-15%). Readers of this handbook may be surprised to see that the annual global mortality of snakebite is between 50 and 100 000 and for scorpion stings about 5 000. Ciguatera fish poisoning is probably the commonest single form of animal poisoning and accounts for tens of thousands of cases of illness each year. The subject of animal poisonings and envenomings is particularly intimidating to non-specialists because of the complex composition of animal venoms, alluded to above, the varied and dramatic pathophysiology of envenoming and the immense geographical diversity of venomous and poisonous species. How can this attitude, and the resulting ignorance, be overcome and the fascination and importance of the subject be communicated to a wider audience of doctors, nurses and scientists in the interests of improving the care of envenomed and poisoned patients? The authors of this handbook have produced a brilliant solution to the problem. They have produced a nearly comprehensive account, containing great detail, rich in literature sources, and arranged in such a clear and logical way as to make the information easily accessible. The handbook is equally sound in its coverage of zoological and medical aspects. An electronic edition would make it possible to locate a particular subject even more rapidly, but even with this hard copy version there should be no problem for a reader, even in the heat of a medical emergency, to obtain the crucial facts in time for them to be useful.

Professor David A. Warrell, MA DM DSc FRCP

Centre for Tropical Medicine & Infectious Diseases

Nuffield Department of Clinical Medicine

University of Oxford

John Radcliffe Hospital

Headington, Oxford OX3 9DU, UK