Snakebite: A Neglected Tropical Disease

More than 3’000 snake species span across many countries worldwide, but only around 600 species are considered to be venomous for humans. Snake families that include venomous snakes are Viperidae, Elapidae, Colubridae and Atractaspididae. They use their venom to hunt and inhibit their prey from escaping by injecting the secretion with the use of fangs. Venom is a complex mixture of many hundreds of toxin isoforms that are mostly various peptides and proteins. Its composition can change not only between species family, but also between individuals, mainly due to different diets, age, habitat, seasonal changes and occasionally sex.

This colourful abundance of toxins has led scientist to develop innovative treatments for hypotension, anticoagulation, wound healing, analgesic and other uses. E.g. Captopril® was developed in the early 1980s from an isolated peptide bradykinin from the viper Bothrops jararaca, and is today used as a drug against high-blood pressure. Not only their venom is useful, but snakes also act as important pest-control against rodents.

Unfortunately, there is a less bright clinical aspect and that is snakebites. Close encounters with humans due to habitat loss and increased urbanization can cause bite accidents. The envenomation patterns can vary widely depending on snake species and the physical characteristics of the victim. Typical envenomation categories range from local swelling and bruising at the bite site, to major organ failure due to one or more of the following toxins:

· hemotoxins (destroy red blood cells, blood clotting and/or blood vessel integrity disruption)

· neurotoxin (inhibit communication between nerves and muscles)

· nephrotoxins (kidney damage)

· cardiotoxin (heart damage)

· myotoxins (necrosis of muscle tissue)

Snakebite has a global estimate of 81’000 to 138’000 deaths per year, resulting from 1.8 million to 2.7 million cases of snakebite envenoming. Researchers assume that the numbers are much higher because in many countries reporting envenomation cases is not mandatory. Furthermore, an estimated 400’000 survivors suffer permanent disabilities like scarring, disfigurement, amputations, blindness and some also post-traumatic stress disorder. The regions with the highest number of casualties are South Asia (121’000), Southeast Asia (111’000) and East Sub-Saharan Africa (43’000). The high number of occurrences in these regions is due to primary agricultural workforce, bad housing and infrastructure, lack of snake-proof footwear or bed nets, poor health services and an increased urbanization with closer contact to snakes.

The only approved cure for snakebite envenomings are animal-derived antivenoms, which neutralize the venom components in a snakebite victim. Antivenoms are generated by immunising horses or sheep with small amounts of snake venom. This is done by capturing venomous species, which are then kept in controlled lab conditions, where their venom is periodically extracted. Small amounts of the crude venom are injected into large animals, like horses, over a period of time. The animal then produces immunoglobulin G (IgG) against a vast number of proteins, including the toxic target molecules. To purify the IgG or its derivative fractionation products (F(ab’)2 or Fab), blood is extracted from the animal and purified. An antivenom can be monovalent if it is specific against one species of snake, or polyvalent if it targets multiple species, but thus lowering the functional specificity of it.

Antivenoms are usually lifesavers. If of good quality and administered soon after the onset of envenoming, there is an increased likelihood of a full recovery. Sadly, antivenom development is very poorly funded and the current method has not changed greatly since its discovery in 1894 by Césaire Auguste Phisalix and Albert Calmette. There are several other problems with antivenoms. Today, some are on the market with no minimum product specifications for dose or effectiveness and may not be appropriately manufactured, making them also dangerous, because they can elicit adverse reactions in patients. They are difficult to supply to poor and rural areas, where it can often happen that a bitten victim is turned away at the hospital door because they have depleted their stock of antivenom. If patients can be treated, they are driven further into poverty and debt, e.g. in 2010 in sub-Saharan Africa an antivenom vile cost from US$ 55 to US$ 640 and in India the cost of initial treatment reached up to US$ 5150. In some cases, patients can develop an allergic reaction to the antivenom. The allergic reaction can range from an itch, a bit of nausea, vomiting to a life-threatening anaphylaxis.

Snakebite victims in rural areas of India or Africa frequently seek help with traditional healers, and thus prolong the time between envenomation and getting effective treatment often with deadly consequences. There are patients who have visited a traditional healer and come back with anecdotal success stories (this is likely due to the bite being from a harmless snake or being a dry bite, where no venom is injected). Then there are other victims that travel for many kilometres to reach a hospital, just to be turned down because of a lack of antivenom. It is no wonder then that individuals will often prefer to seek their familiar traditional healers over a distant poorly supplied hospital facility. There is currently a particular problem in sub-Saharan Africa, since the company Sanofi Pasteur stopped the production of the effective antivenom Fav-Afrique because it was not profitable. This made the current volume of good antivenom on the African market insufficient, allowing for the bad products to be purchased and used.

After years of campaigning and the scientific community gathering proof, in March of 2017 the WHO added Snakebite as a category A neglected tropical disease, amongst illnesses like Leishmaniasis, Rabies and Dengue Fever.
In March 2018 the WHO also adopted the Resolution EB142.R4, that sets out aims on how to confront the snakebite issue.

But what are the concrete changes that need to happen? Educating people at risk on how to tackle and prevent a case of envenomation, by creating programs that teach in schools and village communities. Also, improved health systems are needed for the poorer and at-risk regions, to ensure that antivenom supplies are not quickly depleted and that hospital staff are trained on how to best help the bitten patients. In addition, to provide more first response antivenom units, that can traverse difficult terrain to reach victims quicker to reduce the time between bite and treatment. More research is needed to assess the most effective, safe and cheap antivenoms and search for inhibitors that will help against tissue damaging toxins. The main aim ultimately is to reduce the mortality rate, the life-long disfigurements and the socio-economic burdens that often accompany snakebite victims.

An excellent documentary written and directed by James Reid and produced by the Lillian Lincoln Foundation titled ‘Minutes to Die’ is helping raise awareness amongst scientific communities, public and private health institutions and other organizations about the urgency of this matter.

Recently published material from the WHO shows they are listening. On the 23rd of May 2019 they are launching a strategic roadmap aiming to reduce snakebite mortality and disability by 50%. The roadmap contains four key pillars:

For the WHO to ensure that snakebite is addressed correctly they will also be working together with antivenom manufactures, to rebuild the antivenom market creating accessible, affordable and safe products. With the cooperation of national regulatory agencies and ministries of health they will hopefully be able to promote prevention and create rehabilitation programs helping survivors to overcome the psychological and physiological disabilities, allowing them to return to their work.
 The authorities will engage with local communities in an integrated manner to promote good health practices together with the help of the traditional healers. To quote the WHO: ‘Snakebites, like many other unexpected illnesses, are associated with deity punishment, witchcraft, or other powerfully persuasive phenomena that are often very locally specific. It is therefore important for communities to overcome these misconceptions and create a balance between traditional customs and modern healthcare’.

Finally, they also intend to advance clinical testing of new inhibitors which could be administered by the victim in the field to reduce envenomation’s symptoms, since the highest rate of mortality happens on the way to the hospital (e.g. Varespladib).

This news is encouraging and hopefully the aims will be achieved, but it is just the start. We all need to spread the word through social media and help campaigns raise money to fund these projects.

If you are interested to learn more or help, please visit these websites:

Snakebite: A Neglected Tropical Disease

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