Updated 17.11.2021
Experts on venomous animals, envenomation and treatment, and the related cultural aspects are working to reduce the disastrous effects of these accidents on communities in tropical regions in general and in sub-Saharan Africa in particular. Scientists and practitioners from IRD, the African Society of Venimology and their partners are currently working to assess the situation even as WHO has launched an important initiative seeking to halve the number of victims by 2030.
While the incidence of envenomation is extremely low in temperate regions, where the consequences are well-managed by health systems in developed countries, it represents a real public health challenge in other parts of the world. Envenomations take a serious toll on societies in tropical regions in general, which are home to a denser population of venomous wildlifeAnd larger snakes, which inject larger quantities of venom when they strike.1 and where chances of encountering humans are higher. This is particularly the case in Africa, where major obstacles prevent victims’ access to treatment. At least six million people are bit by snakes each year. These bites result in two and a half million envenomationsHalf of poisonous snake bites and three quarters of scorpion stings are asymptomatic, which means that either no venom is injected, or the amount of venom is not high enough to cause any damage.1, lead to 130,000 deaths, and over 200,000 cases of more or less disabling mutilation, ranging from unsightly scars to limb amputation. Scorpions, which are confined to a smaller geographic area, are responsible for one and a half million stings each year, resulting in 250,000 envenomations and 2,000 deaths. But these figures likely underestimate the true extent of the problem, since most accidents occur in rural areas, far removed from health facilities and statistics, and are therefore not reported to health authorities. However, the major epidemiological and socio-economic consequences of envenomations–particularly those caused by ophidians–led the World Health Organization to add them to the list of neglected tropical diseases in 2017 and to propose a global strategy in 2019 for preventing and combating this phenomenon. Specialists from IRD and the African Society of Venimology are working to improve knowledge about this issue, treatment protocols for patients, while also exploring the cultural aspects surrounding the relationships between populations and wildlife, which are responsible for strong resistance to biomedical care in Africa.
The Black-necked Spitting Cobra - Naja nigricollis -, of the Elapidae family, has a venom mixing cytotoxic, neurotoxic and cardiotoxic substances.
© Luca Boldrini - Flikr CC
Confronting the snake threat
The entire intertropical zone–sub-Saharan Africa, South Asia, Central and South America, and Australia-Melanesia–is exposed to a high incidence of snake envenomation. When addressing the dangers posed by snakes, specialists must consider all the factors involved: the circumstances of the accidents, the way in which each type of snake venom acts on the body, and the treatment of envenomations and associated complications.
Chance encounters
Envenomations are most often the result of an unexpected confrontation between humans and ophids sharing the rural space.
© IRD - Typhaine Chevallier
The many accidents that occur in tropical areas, from the Amazon rainforest to Papua New Guinea and the Sahel, result from an encounter between two protagonists, a poisonous ophidian general group of reptiles comprising snakesand a human being, which happen to be at the same place at the same time. Since snakes do not prey on humans, these confrontations happen unexpectedly, usually resulting from circumstances linked to the sharing of rural areas: for snakes this involves hunting, mating, and the laying and dispersal of young, and for humans this includes activities in fields or plantations. Not surprisingly, most victims are of working age, between the ages of 15 and 45, in the agricultural or herding sectors95% of accidents occur in rural areas.1. And in developing and emerging countries, where health facilities are dispersed in rural areas, this is a major factor in the quality of care.
Humans are not part of the food chain for snakes: the bites are purely defensive.
“In Latin America and in Costa Rica, snake envenomations represent a true public health problem which affects 60,000 and 600 people per year, respectively, primarily population groups in rural areas affected by poverty and social vulnerability, including indigenous communities,” says José María Gutiérrez, a biochemist and immunologist specialised in envenomations at the University of Costa Rica.
Finally, from a logical perspective, the frequency of accidents decreases as the distance between users of rural areas and snakes increases: Western farmers, who use tractors in their work, are less exposed to this risk. Similarly, in societies around the world with primarily urban populations, the rare accidents that occur with snakes are mostly linked to outdoor recreation activities (sports, camping, gardening) or handling reptiles (wildlife, shows, new pets).
The dreaded Viperidae and Elapidae
Echis carinatus, a member of the viperidae family, is a particularly dangerous snake because it is small - and therefore difficult to detect -, it is nocturnal, extremely aggressive and has a very powerful venom.
© Shantanu Kuveskar
600 of the 3,000 known snake species are venomous. Yet the majority of accidents are caused by only ten main species which belong to two families: the Elapidae and Viperidae. The first family includes cobras, mambas, taipans snakes of the Oxyuranus genus present in Australia and New Guinea, bongares snakes of the Bongarus genus, present in South Asia, South-East Asia and East Asia, coral snakes and sea snakes. The second family, which includes various vipers and rattlesnakes, are all poisonous and have fangs that are particularly effective in injecting their venom–they project forward when the snake strikes. “The proportion of venomous species relative to the snake population varies according to the location and environmental conditions,” explains Christian Toudonou, an expert on reptile ecology at Université d’Abomey-Calavi, in Benin. “In the forest regions of West Africa, for example, only 20% of ophidians are venomous, as opposed to 70% in savannah areas.” Depending on their degree of synanthropismdegree of interaction with human beings living nearby, venomous species may or may not be able to adapt to changes in environmental conditions The threat that each one poses will therefore develop in response to the changes associated with human activities. Certain species proliferate in environments transformed by human activity, while others disappear. Even as the threat evolves, it is important to keep in mind that the venoms are impressive hunting weapons.
Cobra or viper syndrome
The spearhead snake (Bothrops asper) is responsible for 80% of envenomations in western Ecuador.
© IRD - Olivier Dangles & François Nowicki
Intended to immobilize, kill and even partially pre-digest prey in order to swallow large animals whole, venoms have various modes of action depending on the snake family. Vipers inject a cytotoxic [rollover: toxic to cells] venom into their prey–or unfortunate farm worker–which is responsible for the viper syndrome. This syndrome is caused by the different types of enzymesMetalloproteinases, serine proteases and phospolipases A2 1 contained in the venom, which provoke immediate oedema, followed by necrosis, which initially affects the local tissue. This form of tissue digestion is the main cause of permanent disabilities associated with envenomations because without appropriate medical treatment it can result in the need to amputate the injured member.
“The occurrence of local and remote vasculo-haematological events in the body are often associated with the loco-regional damage which is specific to the viper syndrome,” says Sébastien Larréché, a medical doctor and biologist specialised in envenomations at the Hôpital d’Instruction des Armées Bégin, in Saint-Mandé, near Paris. “The enzymes and certain proteins in the venom cause damage to the walls of blood vessels, which results in bleeding. Yet they also eventually consume the platelets and coagulation factors, including fibrinogen, which results in haemorrhage at the area of the snakebite and throughout the body.”
Originating from the sub-Saharan rainforests, the Gabonese viper (Bitis gabonica) has the longest venomous fangs and produces the largest amount of venom of any snake.
© Romain Duda
Cobra syndrome, which is associated with Elapidae snakebites, is linked to neurotoxic damage caused by non-enzymatic proteins in the venom, which cause paralysis by acting on the synapses areas of functional contact between two neurons or between a neuron and a muscleto block the transmission of nerve signals. This induces flaccid paralysis throughout the body, eventually paralysing the diaphragm and leading to respiratory arrest. And this entire process can go very quickly, sometimes lasting less than an hour!
Yet nothing is simple. Depending on the species or sub-species, certain venoms can combine several components linked to both syndromes. Cobras, for example, are members of the Elapidae family, yet they have cytotoxic venoms. And certain viper bites cause the same neurological effects as those of Elapidae snakes.
Finally, other damage can occur in the event of viper envenomation: haemodynamic failure–a sharp drop in blood pressure–transient or permanent renal failure, and muscle lysis which can spread beyond area of the bite. Fortunately, scientists and healthcare professionals have developed effective treatment for envenomations and their complications.
Elimination of the venom
The first objective in the treatment of envenomation is to remove the venom from the body in order to stop its harmful effects. “To accomplish this, we administer an antivenom containing antibody fragments against toxins in the venom in question,” Sébastien Larréché explains. “These fragments neutralize the proteins in the venom, which helps remove them from the body and stop the signs and symptoms.”
The management of an envenomation, here the young victim was bitten by an Echis ocellatus, is based primarily on the elimination of the venom from the body by the administration of an appropriate antivenom.
© IRD - Jean-Philippe Chippaux
In reality, it’s a race against time, because the damage associated with the various syndromes occur more or less quickly: the fastest is haemodynamic failure, the drop in blood pressure, which can occur within minutes of the accident and can last for several days. The neurotoxicity associated with cobra syndrome produces its effect within an hour. The vasculo-haematological events occur within a few hours. Necrosis appears after one day, yet in reality the cytotoxicity begins immediately with the oedema surrounding the bite. When it comes to neurotoxic venoms, if the antivenom is administered too late, the bond that has formed between the neurotoxins and neural receptors cannot be separated by the antivenom. Patients must then receive artificial ventilation until the effect wears off on its own–which sometimes takes weeks!
Because in addition to eliminating the venom, the symptomatic treatment is also important. The clinical signs triggered by the venom’s action must be treated. This includes reducing inflammation, compensating for organ failure, treating coagulation disorders, removing necrotized tissue, and resuscitation if necessary... And this aspect constitutes another dimension in the treatment of envenomations.
Treating the body’s reactions
“Eliminating venom from the patient’s body is not enough–or not always–to reverse the effects it has caused,” says Jean-Philippe Chippaux, a medical doctor and herpetologist at IRD, part of the MERIT unit (Mother and child facing tropical infections). “The venom triggers a process which continues afterwards on its own, whether it be necrosis, muscle paralysis or haemorrhage. These phenomena will continue even if the venom has been removed.” Failure of treatment–which, contrary to what was long-believed, is not linked to the quality of the antivenoms–shows that the patient’s body continued to develop certain defence mechanisms that are ultimately harmful for the body, for which specific treatment must be developed.
The venom of ophidians like this rattlesnake (Crotalus), acts as a trigger for internal processes that we can no longer control, such as inflammatory phenomena.
© CC - Jean Beaufort
“Like the inflammatory storm described in severe Covid-19 infections, the venom acts as a trigger for internal processes which are out of our control, such as inflammation, and haemodynamic or renal disorders, and this is what we are working on at the moment,” the expert explains. “Experimental clinical studies are currently underway to assess the role that the destruction of vascular walls by venom from African vipers might play in extensive necrosis or in the runaway inflammatory responses in observed in certain patients. We are looking for early and reliable indicators of particularly serious complications such as renal failure and internal haemorrhage. We are also studying the mechanisms which cause persistent haemorrhagic syndrome, which would allow for more suitable treatment and a better prognosis.”
Of course, rapid medical attention is a decisive factor in the occurrence and severity of these harmful endogenous mechanisms. A patient who comes to a health centre too late might be given dozens of vials of antivenom without any improvement to his or her state, whereas a single vial would have been sufficient if administered early on. “This is why our efforts must exceed the technical framework. We must improve the availability of antivenom in regions with high rates of snakebite envenomation, improve the quality of local treatment, and even the population’s acceptance of receiving biomedical care, especially in Africa, where this remains a major problem,” says Jean-Philippe Chippaux. “WHO and the African Society of Venimology are working to address all of these issues.”
© IRD - Alain Rival
The plantation agro-industry encourages the proliferation of certain snakes. The incidence of envenomations may be 10 times higher among workers in this sector than among those engaged in traditional agriculture.
Risks of envenomation are changing with anthropisation
Humans and ophidians do not mix well: snakes are either eliminated or move away from areas with increasing human population density. And in most cases, the anthropisation of natural environments reduces the density of snake populations and the incidence of envenomations. Therefore, there should have been a significant decline in the number of accidents in sub-Saharan Africa, where human activities are rapidly developing. Yet this is not the case. This suggests that the increase in the human population and the adaptation of certain snake species have combined to maintain the level of envenomations. “A few species, including certain dangerous species like the spitting cobra (Naja nigricollis), forest cobra (Naja melanoleuca), puff adder (Bitis arietans) large vipers (Bitis arietans in the savannah and Bitis gabonica and Bitis rhinoceros in the forest), vipers of the Echis genus and the green mamba (Dendroaspis angusticeps) have a remarkable capacity to adapt to changes caused by the human conquest of natural environments,” says Christian A. S. Toudonou, an expert on reptile ecology at Université d’Abomey-Calavi in Benin. “They thrive in places where human activities result in an increase in the prey included in their more or less varied diet: rodents, birds, amphibians, bats.” The development of an agricultural plantation industry, and the rapid urbanization of the continent, which fosters the proliferation of prey by providing more plentiful food than in natural environments, have contributed to altering the balances in snake populations, often in favour of venomous species like cobras. In plantations, for example, their concentration can be as high as 200 per hectare (as opposed to 10-25 in natural environments), and the incidence of envenomation can be as high as 2,000 for 100,000 workers per year as opposed to only 100 to 200 for 100,000 in traditional agriculture.
The snake threat persists in African cities and the surrounding areas, where urban sprawl creates more areas that are favourable for snakes, and where an abundance of commensal prey is attracted by large quantities of waste. Yet this threat is much is lower than in rural areas. In the Maghreb, the development of scorpion populations is particularly intense, with a high incidence of stings.
Finally, climate change is favourable for snake populations, especially when the environment is hotter, more humid and prey is more abundant.
Living in gardens, homes, villages and even cities, scorpions are a household threat, especially to children.
© IRD - Olivier Barrière
Scorpionism, a domestic threat
Envenomation is not limited to bites. With scorpions, it results from stings… And while these age-old arthropods kill far fewer victims than reptiles, the effects of scorpionism–the term for envenomations by scorpion stings–are a serious public health problem for these societies because the number one victims are young children. The research that has been conducted has already helped to significantly limit mortality in many regions and ongoing tests continue to optimise the treatment of cases of severe envenomation and their specific complications.
A threat in the home
The distribution area for dangerous scorpions is more restricted than that of poisonous snakes. It includes Mexico, southern Brazil, and the Amazon rainforest on the American continent, North Africa, East Africa, and Southern Africa on the African continent, and the Middle East and India in Asia.
Androctonus mauretanicus is a species specific to southern Morocco whose bites are feared
© IRD - Max Goyffon & Claude Grenot
Yet the threat posed by these arachnids is more insidious in that it extends from rural areas to city centres, and even exists within houses. “Certain species feed on household insects, such as cockroaches. They live in our walls, rooms, courtyards and gardens and come out in the evening to hunt. Accidents occur very frequently throughout the entire tropical and subtropical zone,” says Mabrouk Bahloul, medical doctor, intensive care physician and professor at Hôpital Universitaire Habib-Bourguiba de Sfax in Tunisia.
The incidence of scorpion envenomations is therefore at 100 cases for 100,000 inhabitants per year in the Maghreb, which is a global hotspot for scorpionism.
In the Maghreb, scorpionism is a scourge that also strikes in cities and even in homes.
© IRD - Thierry Ru
Out of the 1,500 species identified globally and the fifteen considered to be potentially dangerous for humans, four species are greatly feared there. Androctonus australis, Buthus occitanus, Leiurus quinquestriatus and, more specifically in southern Morocco, Androctonus mauretanicus. They are morphologically characterised by thin pincers and relatively thick tails which contain a venomous apparatus that consists of a vesicle connected to the stinger that is used to inoculate the venom. The scorpion controls this inoculation, but it usually occurs during accidental contact, and often corresponds to a defensive response to the victim placing a hand or foot on the scorpion, or rolling on to the scorpion when sleeping. Most injuries are therefore located in the extremities. While not all stings are venomous, their severity depends in part on the specific scorpion…
Complex venom
“The toxicity of scorpion venom depends on its composition, which is both extremely complex and highly variable,” the specialist explains. “In addition to the species, the scorpion’s age, size, nutrition and even the season can affect the level of danger.”
Buthus occitanus is responsible for a good part of the envenomations by scorpion sting in Maghreb.
© IRD - Claude Grenot
A young and therefore smaller scorpion, for example, has less venom to inject into its victims.
Scorpion venom, which contains toxins that act on the sodium, potassium and calcium channelspores which pass through the membrane of certain cells involved in transmitting electric signals present in excitable cells, as well as on various biogenic aminesmolecule produced in the body which contains an amine groupSerotonin, kinin and histamine in particular1, non-protein substances and various enzyme substances, can act on three levels. They disrupt the nervous system by acting directly on the neuromuscular junction of striated musclescardiac muscle and muscles under voluntary control of the central nervous system, and they also trigger the production of catecholaminesorganic compounds which act as hormones or neurotransmitters, such as adrenaline, noradrenaline and dopaminewhich can reach up to forty times their base value in extreme cases. The venoms can also have a cytotoxic effect on cardiac, brain (only among children), lung, liver and renal cells. Finally, envenomation can lead to inflammatory reactions with varying degrees of severity, which are decisive in the level of severity of the patient’s condition. Due to its low molecular weight, the venom spreads quickly through the body, reaching its maximum concentration in 45 to 60 minutes, before being evacuated naturally by renal excretion. As bleak as this clinical depiction may seem, most scorpion stings are not extremely serious. But this is not true for all patients.
A paediatric hazard
“Mortality linked to scorpionism is two times higher in children than in adults,” Mabrouk Bahloul says. “And severe forms of envenomation in adults often occur among vulnerable patients with comorbidities that worsen the prognosis.” Young children are perhaps more susceptible to scorpion stings because they are unaware of the danger, and play and walk around at the risk of disturbing a commensal scorpion in the home. More importantly, however, children have severity factors linked to their constitution: after the sting occurs, the venom spreads more quickly and massively to other tissues and organs via the lymphatic system and blood circulation in children than in adults.
Children, especially the youngest among them, are the first victims of scorpionic envenomations because there are factors of gravity related to their own constitution.
© IRD - Olivier Barrière
“This significantly higher tissue affinity in children is primarily due to the ratio of the venom injected to the child’s weight or body surfaceData that is more precise than weight, used in paediatrics to calculate the concentration of an active principle in the body, especially to define the dose of a treatment.1, which is relatively higher than it is for adults,” the specialist explains. Therefore, for the same dose of injected venom, the serum level will be higher among children, which results in a greater cytotoxic effect and inflammatory reaction. “In addition, the density of the voltage-gated sodium channelschannels in which the opening depends on the electric potential of the membrane is higher among children, which results in a higher sensitivity to the venom’s action on the nervous system through a massive discharge of neurotransmitters such as adrenaline,” he explains. All of these specific characteristics explain why the clinical picture is generally of greater concern in the paediatric population. The intensity and multiplicity of the clinical signs can be used to characterize the severity of the envenomation and any possible complications.
Polymorphic clinical signs
Close-up on the chelicerae of Androctonus australis, which are the characteristic mouth appendages of arachnids
© IRD - Max Goyffon & Claude Grenot
In most cases, 90 to 95% of the time, the clinical picture associated with scorpion envenomation is limited to isolated local signs. In this case, specialists refer to a stage 1 benign envenomation and recommend symptomatic treatment–with analgesics–without hospitalization. Yet in 5 to 10% of cases, the clinical picture also includes general and digestive signs, without being life-threatening: this is stage 2, moderate envenomation. These general clinical expressions–fever, agitation, excessive sweating, priapism and chills–are linked to dysfunction of the autonomic nervous system. The system is distressed by the massive discharge of catecholamines and the inflammatory syndrome. The digestive signs, vomiting, diarrhoea, hypersalivation, bloating, and abdominal pain are more frequent among children and their occurrence also depends on the type of scorpion. “At this stage, administering a specific antivenom serumThis is a specific anti-scorpionic serum for the species present in the region. In Tunisia, this bivalent serum can be used to treat envenomations from Androctonus australis, and Buthus occitanus. It must be administered within thirty minutes of the sting, at the latest three hours after the sting.1 is recommended, in addition to the symptomatic treatment,” says Mabrouk Bahloul. And hospitalization is necessary to observe the patient for 24 hours.
Heart failure
Yet in 1% to 2% of cases, envenomation is much more severe and leads to respiratory distress caused by a pulmonary oedema resulting from heart pump failure, or even a state of shock and neurological signs.
Scorpion venom can lead to severe cardiac complications, related to its myocardial toxicity, violent adrenergic discharge associated with envenomation and the myocardial ischemia that may result.
© Hôpital Charleville-Mézières
“Three mechanisms can contribute to this heart damage: the myocardial toxicity of the venom itself, the adrenergic discharge which speeds up the heart rate–adrenaline, noradrenaline and neuropeptide Y, a neurotransmitter, can increase up to 100 times their normal rate–even causing heart failure, and myocardial ischemiadecrease in arterial blood flow to the heart linked to the failure caused by a racing heart,” says the scientist. This is stage 3: immediate hospitalization in the intensive care unit is required, as well as the administration of antivenom serum. Oxygen therapy, with or without mechanical ventilation, is required, in addition to antivenom and symptomatic treatment. “In North Africa, when venoms lead to heart pump failure, our clinical research has revealed the need to administer dobutamine to strengthen myocardial contractility and restore blood flow to the heart,” he explains. “Whereas in India, where the scorpion venom causes generalized vasoconstriction, we use vasodilators.” Research conducted recently by intensive care units at the Sfax and Monastir hospitals in Tunisia has made it possible to characterize the nature of the heart damage related to the local scorpions and optimize treatment in this important area. Moreover, in the end, normal cardiac function is restored for most patients, and they can leave the hospital after five days.
Neurological damage
Tunisian hospitals have contributed to the development of protocols for the management of complications, which have drastically reduced the mortality associated with scorpionism.
© OMS
Neurological complications are frequent in children in stage 2 and 3 envenomations. They occur in the form of muscle disorders (agitation, muscle spasms, convulsions) or brain disorders (coma that is more or less deep). The latter, associated with poor prognosis, is caused by haemodynamic dysfunction following autonomic nervous system dysfunction. Among very young children, for whom the blood-brain barrier is still permeable, there is the possibility of neurotoxins from the venom acting directly on brain function.
“While the young age of the patients (under five years old) represents a poor prognosis factor, mortality has considerably dropped in recent years in Tunisia with the standardization of treatment protocols and the availability of specific, locally-produced antivenoms. Thanks to this, we have only recorded a few deaths, between one and five out of the annual 30,000 to 40,000 envenomations,” he says.
© IRD - Catherine Paquette
In Mexico, where 289 of the 1500 known species of scorpions live, accidents are very frequent, especially in poor areas.
Mexico wins the fight against scorpion envenomations
Mexico, a true hotspot for scorpionism, has succeeded in effectively containing this health burden. “The medical authorities in Mexico, who were aware of the major health challenge of scorpion envenomations, began to take this issue seriously over a century ago,” says Jean-Philippe Chippaux, a medical doctorand herpetologist at IRD. And their efforts have proved successful!” The incidence rate of scorpion accidents is very high in this country: 230 stings per 100,000 inhabitants per year, and 300,000 stings treated each year in Mexican health centres and hospitals. This rate is higher in certain regions, the centre of the country and Pacific coast. Scorpion populations develop in populated areas, especially in poorer areas, and in most cases, stings occur in houses. “The number of stings has remained stable since the mid-2000s,” the specialist says. “But mortality has dramatically declined.” It has dropped from 1,500 deaths per year in the 1970s to less than 50 annual deaths today. “This progress is directly linked to continuous improvements in hospital care, the use of locally produced antivenoms composed of highly purified antibody fragments–which are more effective and better tolerated–and better access to health services for the majority of the Mexican population,” the scientist says.
The green mamba (Dendroaspis viridis) is an arboreal elapid that has adapted well to anthropized environments. Extremely fast and with a powerful neurotoxic venom, it is the cause of many fatal accidents in Africa.
© IRD - Jean-François Trape
Antivenoms, the first line of treatment
Although envenomations were once tragic and often fatal, specific treatment is now available due to the discovery of antivenom serumsliquid component of blood from which coagulation factors have been removed. The first one was developed in 1895 by physician Albert CalmetteAlso co-inventor, with Camille Guérin, of the tuberculosis vaccine which targets the pathogenic agent responsible for the infection, Bacillus Calmette-Guerin (BCG).1, thanks to pioneering work by Louis Pasteur on immunotherapy, and was effective against cobra venom.
Dissection of venom glands of snakes Naja tripudians and Bungarus fasciatus for the preparation of anti-venom serum at the Pasteur Institute in Saigon around 1900
© Institut Pasteur
While the basic principle and production techniques for the serums have not changed in over a century, significant progress has been made in the methods for improving the quality, effectiveness and tolerance of the serums. “Scientific research in this area has now taken various directions,” says Jean-Philippe Chippaux, a medical doctor and herpetologist at IRD. “From a technological perspective, the research aims to develop and synthesize a universal product for all types of venom. Other, more pragmatic research is focused on improving the availability, accessibility, and acceptability of existing effective serums for groups that are most in need.”
Immunity concentrate
When it comes to rapidly eliminating venom from the body of a victim of envenomation, nothing is as effective as experienced immune agents! Based on this principle, scientists came up with the idea of hyperimmunizing animals by subjecting them to repeated doses of venom and then collecting their antibodies which are specialized in fighting the toxins contained in the venom. It can then be administered to a patient who has been stung or bitten to treat the envenomation.
Handling of a scorpion, held by a laboratory instrument over a container, with a kind of syringe to collect its venom.
© OMS
“The antibody fragments selected are very specific to the venom to be treated. They will form complexes with its proteins to help eliminate its removal from the body,” says Sébastien Larréché, a medical doctor and biologist specialized in envenomations at Hôpital d’Instruction des Armées Bégin.
The simple and ingenious principle has been the same since the therapeutic approach was first developed by Pasteurians. Large animals are used for the immunization in order to produce large quantities of plasma liquid component of blood containing serum and coagulation factorsand immune agents. Equines, sheep and camelids are currently used to produce these antibodies. Camelids in particular are of special interest because they synthesize smaller antibodies which are better tolerated by patients’ bodies. Tolerance to antivenoms is indeed a significant issue in order to avoid administering serums that make the patient just as sick as the venom...
Purification and tolerance
A drop of venom at the end of the fangs of a striking viper (Bitis arietans), a venomous snake with fangs that can exceed 4 cm in length. Its bite is fatal and local complications are often very important.
© IRD - Jean-François Trape
Antivenom serums have had a long–often justified–reputation of causing serious anaphylactic reactionsallergic shock with serious and even life-threatening consequences in patients who receive the treatment. Their use has often required treatment of serious adverse effects in addition to the symptoms linked to the envenomation. To such an extent that healthcare professionals sometimes questioned their therapeutic benefits. The problem was in fact linked to the raw antivenom serum, which contained several proteins without antivenom properties that were highly allergenic. “But the improvement of purification techniques and a greater understanding of the most dangerous proteins contained in the antivenoms has enabled the development of much safer products with improved effectiveness,” says Jean-Philippe Chippaux.
Collection of venom from Bungarus candidus, a snake of the family Elapidae commonly called Bongare candide, by herpetologist Alison Piquet.
© IRD - Jean-Yves Meunier
Today, in fact, well-made antivenoms only contain specific whole immunoglobulins G (IgG)a type of antibody or fragments of immunoglobulins G–which have the advantage of being better tolerated than whole IgGs–that are tailored to the toxins of the targeted venoms, to the exclusion of any other proteins. The frequency of adverse effects has dropped considerably, while the venom neutralization potential has significantly improved. As long as the right antivenom is used...
Regional versatility
Although these pioneers believed they had found a universal treatment in their anti-cobra serum, it quickly became clear that each venomous species, both snakes and others, had a very specific venom, with its own complex biochemical cocktail of toxins and harmful enzymes. The animals producing the antibodies must therefore be immunized with the venom of each targeted species in order to obtain antivenoms suited to each specific threat. And since it is not always easy to identify the species responsible for the accident, antivenoms are now versatile and are used to treat all the snake and scorpion threats in a given region: they combine immune factors that treat the various venoms present in the area.
Harvesting of scorpion venom at the Pasteur Institute of Tunis, to develop anti-scorpion serum
© Institut Pasteur
The anti-scorpionic serum produced in Tunisia at Institut Pasteur, for example, is effective against both Androctonus australis and Buthus occitanus, the country’s two dangerous species.
The specific nature of the venoms makes designing and producing antivenoms a complicated process. It requires keeping collections of living venomous animals for samples–or working with reliable venom extractors–purifying the venoms using sophisticated biotechnology, maintaining equine stock to be immunized, and conducting research on the venomous animals–both reptiles and arachnids–present in the target area for the product… Furthermore, to simplify distribution and conservation in remote tropical regions, where 95% of envenomations occur, and ensure they are transported and stored without having to maintain a cold chain, antivenoms should ideally be stored in lyophilized state.
Costly accessibility
For all these reasons, antivenoms are as costly to develop as they are to produce. Certain countries with a high incidence of envenomations have decided to manufacture their own antivenoms. Historically, this has been the case in Mexico, Brazil, Costa Rica and India, where the serums are manufactured to suit to the country’s native venomous species.
Requiring extensive logistics to obtain venom and antibodies, purify, package and distribute the products, quality antivenoms are expensive.
© IRD - Jean-Yves Meunier
“However, despite the pervasive threat posed by snakes in sub-Saharan Africa, this region of the world has only one laboratory, in South Africa, which produces antivenoms for its national market only,” says Jean-Philippe Chippaux. “This vacuum has led many manufacturers to develop products of poor quality or sell antivenoms with antibodies for species that are not present in Africa!” A few Western pharmaceutical laboratories have developed versatile serums tailored to African venoms. However, in the absence of a solvent local market, most have abandoned these projects in recent years, and converted their production lines to manufacture vaccines, even before the start of the Covid-19 pandemic.
Sub-Saharan obstacles
The cost of antivenoms therefore makes them inaccessible for African patients. “An average treatment costs between 50,000 and 180,000 CFA€75 to €2701 francs depending on the quantity of antivenom required, the severity of the envenomation, and the lapse of time before accessing biomedical care,” says Blaise Adelin Tchaou, an anaesthetist-intensive care physician and teaching hospital practitioner at Centre Hospitalier Universitaire Borgou-Alibori, in Parakou, Benin. This teaching hospital practitioner is participating in research aimed at assessing the severity of haemorrhagic complications and treating kidney failure resulting from envenomations.
Agricultural work, such as collecting vetiver stems - an artisanal raw material - in the Dapaong region of Togo, is the occasion for disastrous encounters with the venomous snakes that populate the natural areas.
© IRD - Typhaine Chevallier
Since most of the victims are workers in the agricultural sector, farmers or livestock farmers, the cost of treatment is a major obstacle to accessing care. The funding for these high-tech products cannot only be dependent on the resources of rural populations in sub-Saharan Africa, where the average monthly income rarely exceeds €30 per household. “New initiatives have emerged here and there to improve access to antivenoms using public subsidies in Togo, Cameroon, and Burkina Faso, or to organise community-based solidarity efforts with deadlines for collecting the fees for the treatment which is compatible with traditional savings,” Jean-Philippe Chippaux explains. “Yet the obstacles are greater than the financial aspect only, they are also linked to training for healthcare professionals, the organisation of pharmaceutical logistics, and cultural aspects that are deeply ingrained in society.” The mobilization launched by WHO against snake envenomations seeks to address these different areas.
Dosage and enzyme inhibitors
“Since antivenoms are expensive and because the use of high doses can increase the risk of poor tolerability, research is currently being conducted to optimize administrative protocols and determine the right dosage for each case,” says Sébastien Larréché. “The goal is to define the quantities of product needed to quickly eliminate all of the venom.” The research therefore involves developing diagnostic tests to assess the severity of the envenomation, which would identify the patients who need more antivenom or another dose within hours or days of the accident.
Handling of Bitis arietans snake venom samples at the Institut Pasteur de Côte d'Ivoire in Adiopodoumé, in 2017
© Institut Pasteur - Nabil Zorkot
Another innovative approach involves identifying the inhibitors of certain enzymes contained in the venoms. The enzymes act by modifying the chemical structure of substances present in the body to give them a toxic action. Some are responsible for major haemostasis [nr: all of the mechanisms which contribute to stopping bleeding] disorders, while others contribute to necrosis. “Yet what is interesting is that some, such as phospholipases A2, are common to venoms from Viperidae and Elapidae. The inhibitors of these enzymes therefore represent a relevant key for developing a universal synthetic antivenom. However, the effects proven on animal models must still be confirmed with humans,” says Sébastien Larréché.
© OMS
A major health issue in tropical areas, envenomations represent a substantial part of admissions to hospitals.
Global strategy and African initiative
Enough is enough! “In order to halve the number of deaths and disabilities caused by snake envenomation by 2030, the World Health Organization developed a specific strategy in 2019 to prevent and combat this phenomenon,” says Jean-Philippe Chippaux, a herpetologist and medical doctor at IRD. The strategy is made up of four main components aimed at informing and mobilizing communities to prevent envenomations and increase the use of treatment, ensuring access to safe and effective treatment, integrating the treatment of envenomations by strengthening health systems and creating a global coalition to promote and finance this strategy, and accelerating research on new treatments, diagnostic products and medical interventions. “The accessibility to treatment component targets Africa first and foremost, due to the enormous gap that exists there between envenomation challenges and the resources needed to treat them. On the other hand, the product improvement component targets Asia, where the quality of antivenom products is often inadequate,” the specialist explains.
Just like the coalition established to combat HIV, tuberculosis and malaria, this approach seeks to mobilize abundant resources from major NGOs, international foundations and other generous donors.
“But sub-Saharan Africa, which is the epicentre for snake envenomation, has its own characteristics and constraints,” says the researcher. “To better respond to this challenge, the African Society of Venimology advised WHO to adapt its global strategy to the local context.” This organization, which brings together over 200 African researchers and practitionersIn both French-speaking and English-speaking Africa.1, would prefer to develop local resources, find funding mechanismsBy mobilizing States, local authorities as well as companies–including in the agro-industrial field–in which workers are overexposed to these risks.1 or ways to reduce costs in order to make treatment more accessible. “Because for African patients, the issue is not creating access to new, high-tech antivenoms resulting from future innovations, but simply to ensure access to existing and proven products nearby, in physically realistic accessibility conditions,” the researcher says.
Biomedical management of envenomations, including administration of antivenom and treatment of symptoms, faces cultural and practical barriers in sub-Saharan Africa.
© IRD - Philippe Bousses
The cultural equation in sub-Saharan Africa
Snakebites did not come into being with the invention of serums and biomedical care! Through the ages, human societies, especially those more exposed to the threat of snakes, have developed representations, practices and beliefs linked to snakes and envenomations, some of which still exist today. “In sub-Saharan Africa, these cultural systems are in part an obstacle to access to biomedical care or its effectiveness, and act as substitute when it fails,” says Jean-Philippe Chippaux, a medical doctor and herpetologist at IRD. “And although anthropological research is only just starting on this topic, it is vital in supporting any policy aimed at making appropriate care available for all patients.”
The bite of Echis ocellatus, a viperid widespread from West Africa to Central Africa, is very often fatal without proper care.
© IRD - Jean-François Trape
Understanding and integrating cultural factors is therefore a prerequisite for convincing the patients, healthcare workers, affected rural populations, and even traditional healers of the merits of treatment combining antivenom with clinical treatment of the symptoms and complications linked to envenomations. Researchers, anthropologists and specialists on African societies are currently investigating this area...
Dread of reptiles
“There are sometimes major differences from one society to another in the reactions to the chance occurrence of an encounter with a snake. In many societies, the encounter is seen as a bad omen, a fateful sign from the spirit world. On the other hand, among certain pygmy hunters, it can be seen as the great fortune of having found a hunted animal, especially if it is a python or large viper,” says Romain Duda, a post-doctoral anthropologist at Institut Pasteur, specialized in relationships between humans and animals in Central Africa. “Yet there are also recurring issues, common features in all human societies related to the snake’s place in mythological stories and collective fears, as has been established in research in evolutionary anthropologya field of interdisciplinary research combining analysis of genetics, cognition, linguistics, cultures and social systems to study the history of humanity in terms of its evolution.”
For some pygmy hunters, the encounter with a python (as here) or a large viper is above all an opportunity to bring back a prized ophidian meat.
© Romain Duda
This is because snakes have always been a threat to our species and for great apes. Research has shown that these reptiles generate an innate fear in all primates, including humans. According to the snake detection theoryA hypothesis proposed by researchers in evolutionary psychology in the 1970s, based on research by anthropologist Lynne Isbell, and recently cited again in work on infants’ reactions to seeing snakes or spiders.1, this could even have had an impact on our evolution, including our visual abilities to identify specific snake movements.
“This animal has always been a predator, capable of killing us and, what is more, doing so quickly, which is not trivial,” the specialist says. “Two factors also affect the local representations: the snakes’ morphology and behaviour.” Because in many societies, animals with an unusual form or behaviour compared to other species in the animal kingdom are given a special status in the pantheon of local wildlife. This is true for nocturnal birds, hybrid animals such as marine mammals, and chimpanzees and gorillas, which are close to humans. The same is of course true for snakes.
A unique symbolic position
“This singular nature, which exists in relationships between the human species and snakes, could explain the snake’s place in questions surrounding the world’s origins and major foundational stories in many societies,” says the specialist.
An Egyptian cobra, also called Egyptian naja, (Naja haje) in attack position. This elapid, present in most of Africa and in the Arabian Peninsula, is dangerous by day and by night.
© IRD - Jean-François Trape
For several population groups in central Africa, such as the Mpiemu people in the Central African Republic and the Beti people in Cameroon, the history of their ethnic group highlights the snake’s key role: their ancestors crossed a certain river on a snake’s back to reach the place where their descendants now live. It is worth noting that comparable narratives involving snakes also exist in South America and in the Amazon. In addition, evangelization of the global south exported Biblical myths surrounding the snake’s sulphurous role, and its association with disastrous diabolical intentions…
In this context, where mythology and beliefs are often intermingled, an encounter with a snake–and a resulting bite–is not necessarily seen as a chance or accidental occurrence. “In the rural communities of Benin, as in many other African contexts, there are two distinct ways of viewing envenomations,” says Roch Houngnihin, an anthropologist at Université d’Abomey-Calavi who works on the perception and treatment of snake-related accidents in his country. “There can be several criteria used to qualify them and this will influence the choice of the therapeutic remedy–if economic factors and the availability of biomedical treatment allow such a choiceDue to a lack of serum in high-prevalence areas–far from urban centres which are better equipped with health facilities–and their high cost, this option is not always available.1, which is not always the case.”
Natural and supernatural bites
Depending on the reptile species, the immediate consequences of the accident, and the persistence of clinical signs, a snake envenomation may be perceived as a natural occurrence or, conversely, be associated with the realm of witchcraft.
Dangerous species of snakes are paradoxically considered harmless in some rural communities in West Africa, where their bite is considered witchcraft and not an accident.
© IRD - Jean-François Trape
“Certain snakes–despite being venomous–are considered harmless in rural communities,” the researcher says. “If they happen to bite, it is seen not as an accident but as sorcery, a spell cast by a third party. In keeping with this logic, a health centre is not the right authority for handling this accident. Who better than a traditional healer to heal a bite caused by witchcraft?”
Two other factors, the “peak in severity” and “late healing” factors help determine the mystical origin of the accident and argue in favour of a healer’s assistance. The first factor corresponds to the emergence of severe symptoms in the hours following the snakebite. The second confirms the supernatural nature of the envenomation and the choice of seeking assistance from a healer due to the persistence of severe clinical signs several days after the accident… “Among the Baka pygmies in Cameroon, if a snakebite is deadly, it is almost systematically associated with an attack caused by sorcery,” says Romain Duda. “This is not the case if the bite is not fatal.”
These criteria, which are almost always associated with accidents involving the poisonous snakes present in sub-Saharan Africa, impel the vast majority of patients–80% in Benin, even more elsewhere–to turn to healers first.
In the absence of appropriate biomedical care nearby, 80% of envenomated victims in sub-Saharan Africa are treated by traditional healers, who are often better at reassuring than saving.
© IRD - Jean-Jacques Lemasson
Traditional specialists
“Although there are fewer of these healers than those dedicated to ailments that are more common in rural areas, such as malaria, wounds and fractures, almost all villages have a healer specialized in envenomationsAccording to the National Policy of Benin Pharmacopoeia and Traditional Medicine report (Politique nationale de la pharmacopée et de la médecine traditionnelle), 2019, from the Benin Ministry of Health.1,” Roch Houngnihin explains. “Their intervention relies on the use of medicinal plants believed to be effective against envenomations, often prepared in powder form to be ingested or applied to scarification on the skin surrounding the wound.” Their treatment also involves cultural borrowings such as the use of tourniquets or the black stone (see Box), and instruments and techniques once used by Western Christian missionaries in tropical regions, of which the clinical efficacy has since been disproven. “We have begun research on the plants used in traditional medicine, to establish an inventory, taxonomic identification, and eventually assess their actual pharmacological properties and even their molecules of interest,” the scientist says.
Sacrificial altar of a Fon healer - practitioners who can be called upon to treat and interpret the meaning of envenomation in Benin.
© IRD - Marc Egrot
The treatment provided also relates to the management of the magical aspects of the envenomation. This includes different rituals and practices depending on local beliefs. In southern Benin and neighbouring Nigeria, the cultural region of the Fon and Yoruba peoples, a diagnosis is performed by a practitioner of Fâ divinatory geomancy to determine whether the bite is of natural origin and the effective methods of treatment. In this region and elsewhere, treatment of the spell often involves codified protocol. “The exorcism requires the symbolic removal of the snake ‘tooth’ from the wound once the symptoms have disappeared, with sacrificial rituals and invocations,” Roch Houngnihin explains. “Often the nurse at a health centre will advise the patient who has received treatment to return to their village afterwards to have the snake tooth removed by a specialized healer to reinforce the healing.”
The distribution of roles between traditional medicine and biomedical care is far from simple.
Comforting more than saving patients
“The corollary to problems linked to the availability, quality and accessibility of antivenom serums, and even the competence of the health workers, is that African health structures suffer from a lack of trust when it comes to the treatment of envenomations,” says Jean-Philippe Chippaux. “And in most cases victims are advised to seek assistance from traditional medicine, which is better suited to offering comfort than to saving lives.”
The risk-benefit calculation of preferring the intervention of the village healer may arise, when the first dispensary - where the availability of antivenom is rather hypothetical - is several hours away by motorcycle.
© IRD - Typhaine Chevallier
“Yet it is important to avoid underestimating the psychosocial support provided by the healer in a village,” says Romain Duda. “The healer can quickly reassure a patient and prevent them from panicking or becoming agitated, which is very valuable in improving the patient’s general condition. The benefit-risk of the opting for the healer’s intervention must also be considered, especially when the closest dispensary–where the possibility of receiving care is dependent on the hypothetical availability of antivenom–is hours away by motorcycle!” Moreover, populations do not see modern medicine as an alternative to ancestral medicine, but rather as a complementary approach. They can therefore easily combine assistance from one or the other, seeking assistance from the health centre for “natural envenomations”, for example, and from the traditional healer for “supernatural envenomations”. Or, more pragmatically, by choosing one form of medicine over the other based on the availability of treatment, the apparent severity of the signs and the means they have available, as has been demonstrated in research conducted in Benin.
Therefore, traditional medicine is and will long remain an inseparable part of the issue of envenomations in sub-Saharan Africa.
Working with healers
As true experts on the social and cultural aspects involved in treating snakebites, traditional healers are indispensable partners in any health policy in this area. They are well integrated in the social and economic fabric of care, especially in rural areas, and are trusted by the majority of the population. Their support must be negotiated because they are very active in maintaining their position vis-à-vis the health centres. “These individuals must absolutely be involved in the prevention strategy for fighting envenomations coordinated by WHO to reduce mortality and disability linked to snakebites in Africa,” says Jean-Philippe Chippaux. “This is an essential condition in ensuring the acceptability of the biomedical approach and widely promoting it in the societies affected.”
Few rural health centers in sub-Saharan Africa, even though they are the closest to the majority of envenomated victims, have antivenoms adapted to the snakes of the region and health care personnel accustomed to using them.
© IRD - Michel Fromaget
But there is also a need to redouble the efforts in research in the social sciences. “There is still relatively little anthropological research available on snake envenomation, its practices and the different populations’ representations of snakes,” says Romain Duda. “Remedying this scientific information gap is vital in understanding individuals’ different reactions following a bite or even visual contact with a snake, and in understanding the meaning associated with these events. This knowledge will be invaluable in supporting the component of the global WHO strategy aimed at ‘informing and mobilizing communities in order to prevent snake envenomation and increase the use of treatment.’”
© Canal blog
Despite its scientifically proven ineffectiveness in treating envenomations, the black stone continues to be used in remote health centers and by village healers.
The Black stone, White fathers and placebo effect
Brought by Jesuits from the Far East during the 17th century, the black stone was widely distributed starting in the late 19th century by the White Fathers [note rollover: Western religious missionaries] to treat snake and scorpion envenomations in Africa. Since then, it has been a great success there. It can be purchased at pharmacies, it is frequently used by traditional healers, and is even used at health centres in some remote areas. The black stone, a rudimentary medical instrument, often counterfeited locally, is a fragment of bone which has been slowly charred in low-oxygen conditions (like charcoal). It is placed on the snakebite to absorb the venom. “The black stone sticks to the skin, as if it were sucking the venom, then it falls off, giving the impression that it has extracted the evil,” says Romain Duda, a post-doctoral anthropologist at Institut Pasteur. “Other than providing a symbolic extraction of evil, it cannot remove the venom. If the victim has received a deadly dose of venom, they will eventually succumb to it. If it was a dry bite, without any substantial injection of venom, the victim will recover, survive, and the healing will be attributed to the black stone.”
The black stone was in fact proven to be ineffective by Francisco Redi, the father of toxinologydiscipline studying venomous animals and venoms, as early as the 18th century, following experiments conducted between 1662 and 1671. This result has been confirmed by recent scientific research on the subject: experimentation conducted in vivo on model animals proved that the black stone extracts less than one thousandth of the venom injected, regardless of whether it originated from a viper, cobra or mamba! Its action is therefore not strong enough to affect the prognosis of an envenomation or even have any effect in relieving the symptoms. The most that can be expected is a placebo effect.
