Snakebite envenomation: the deadliest of NTDs

Every hour about 15 people die in the world from snakebite envenomation, the deadliest neglected tropical disease, which mainly affects the poorest

Snakebites are a neglected public health problem in many tropical and subtropical countries. According to the World Health Organization (WHO), each year there are about 5.4 million snakebites, causing between 1.8 and 2.7 million cases of envenomation, of which, between 81,000 and 137,000 result in deaths and approximately three times more, lead to amputations and other permanent disabilities. Snakebite envenomation, leishmaniasis and African trypanosomiasis are among the deadliest Neglected Tropical Diseases (NTDs) worldwide. Although preventable, death by snakebite demands a quick response, but unfortunately for most victims, access to care is very difficult. In addition, there are socioeconomic and cultural factors that influence the search for treatment and cause many victims to opt for traditional practices instead of seeking to hospital care. Most cases occur in Africa, Asia, and Latin America. In Asia, up to two million people are poisoned  each year, while in Africa there are an estimated 435.000 to 580.000 who need treatment annually. Snakebites tend to occur more frequently in women, children, and rural workers from poor communities in low- and middle-income countries, with weak health systems and few medical resources. The effects are usually more severe in children, who have less body mass.

Professor Emeritus of the Instituto Clodomiro Picado and Faculty of Microbiology of the University of Costa Rica, Dr. José María Gutiérrez, admits that snakebite envenoming is a relevant public health problem in Costa Rica, as well as in the rest of Central America. According to him, in his country, there are about 500 cases of snakebites per year, which corresponds to an incidence of 10 cases per 100.000 inhabitants. Among them, from one to four people die annually as a result of these envenomations. “An unknown number of people still develop physical and psychological sequelae, an aspect that needs to be further studied and managed. Most cases occur in the humid plains of the South Pacific, Caribbean, and northern regions of the country, predominantly affecting rural health workers,” he adds. Most accidents, and the most serious, are caused by the viper species Bothrops asper, known locally as terciopelo.

Dr. Abdulrazaq Habib, infectious and tropical disease physician and epidemiologist at Bayero University, Kano, Nigeria, acknowledges that in West Africa snakebite is also a major medical problem, accountable for substantial morbidity, mortality, and public health burden. “In the sub-region, it is estimated that about 5 thousand people die annually from snakebites. The load is highest in the savannahs of Nigeria, Ghana, Burkina Faso, Cameroon, Côte d Ivoire and Niger. The other countries also report morbidity and mortality, he points out. Also according to him, the issue was neglected and did not have proportional resources allocated for control, despite representing a modestly high burden on the West African sub-region. “West African governments have not responded to the problem. Although there are competing priorities in these countries, the allocated resources remain excessively small when compared to other diseases with similar or even lower burdens, for example, Buruli ulcer, intestinal nematode infections, leishmaniasis, onchocerchiasis, trachoma and trypanosomiasis, says Dr. Abdulrazaq while adding that funding is a major challenge and should be substantially increased to improve care and research. In 2020, a study published in PLoS Neglected Tropical Disease, where Dr. Abdulrazaq was lead author, revealed that Nigeria would need to spend about 63 times more on snakebite drugs, while Burkina Faso would need to increase its spending by a factor of 11 to achieve the goals agreed by the WHO.

In Nepal, according to Dr. Sanjib Kumar Sharma, Professor of the Department of Internal Medicine and snakebite expert at Institute B. P. Koirala of Health Sciences (BPKIHS) in Dharan, due to the high density of people and snakes living in plain (Terai) region of Nepal, Snake-human encounter leads to the frequent occurrence of bites. In addition, the habit of sleeping on the floor in Terai also predisposes residents to nocturnal bites. There are several species of highly venomous snakes in the Terai, such as Naja naja (common snake), Ophiophagus hannah (King cobra), Bungarus caeruleus (common Indian krait), Bungarus fasciatus (banded krait) and Daboia russelii (Russell viper, restricted to western Nepal).

Although snakebite incidents and resulting deaths are common in Nepal, the issue still remains grossly neglected and experts call it an invisible crisis on the prowl. Underreporting is a common problem. To get an idea, data from the Ministry of Health and Population show only about 20 thousand annual snakebite and 1,000 deaths caused by snake bites, while the article published in March entitled Snakebite epidemiology in humans and domestic animals across the Terai region in Nepal: a multicluster random survey”  reveals a very high adjusted incidence rate of bites (251 per 100,000), 49% envenoming and 7.8% lethality. “Among the victims, women and children accounted for 3/4 of the deaths. This extrapolates to 26.749 37.661 people bitten and 2.386-3.225 deaths each year – much more than previously estimated,” says Dr. Sharma. Also according to him, the extent of amputations, surgeries and disabling sequelae is impressive. “The high frequency of psychological symptoms reported, such as anxiety or fear of returning to the accident site, highlights the need for mental health support,” he adds while emphasizing that snakebite is certainly the deadliest of NTDs, and an important contributor to mortality, physical and mental health in Nepal, as observed in this epidemiological study, the first on the topic conducted in the country that covered the entire rural Terai and applied an original methodology that included the One Health approach.

In Brazil, according to data from the Ministry of Health, in 2020, 31,395 snake accidents were registered in the official systems, of which 121 led to the victims death. The jararaca is responsible for 70% of the accidents; followed by the rattlesnake, about 9%; surucucu 1.5%; and true coral with less than 1% of the records. Most of these accidents affect higher risk groups, such as rural workers and Indigenous populations. The country stands out for snakebites, especially in the Amazon region. To get an idea, in 2016, of the 26,244 notifications of the type, more than 8.6 thousand were in northern states, according to data from the Information System for Notifiable Diseases of the Ministry of Health (Sinan/MS). Currently there are about 30 thousand accidents recorded per year, and this number should be higher, since many cases are not reported. Some studies carried out in the Amazon have demonstrated the existence of underreporting, especially in communities more distant from urban centers where the most vulnerable populations are concentrated and the ophidian accident is relatively more frequent. In Rio Grande do Sul, the number of accidents registered with rattlesnakes increased significantly and the mountain areas of Rio de Janeiro has faced an infestation by snakes, among them, the rattlesnake.

The professor of the Multidisciplinary Center, Floresta campus of the Federal University of Acre (Ufac), Dr. Paulo Sérgio Bernarde, emphasizes that amid the different facets that the ophidian accident can show in each region, it is essential that the existence of “invisible” populations living in relatively more distant communities and where the accident is a constant danger, pay special attention to solving the problem. “These populations considered invisible need to enter epidemiological statistics so that the scale of the problem is officially noted by governments health programs. We suggest improvements in demographic censuses and in the collection of epidemiological data in these regions where these failures occur. In this way the authorities can be charged in relation to the needs of this population, defends the researcher.

Lack of data

Epidemiological data on snakebites are scarce. In Ceará, for example, the only report on the subject was last published in 1997. However, according to the Notifiable Diseases Information System (Sinan), more than 13 thousand snakebites have been registered since 2001 in the state. An unprecedented study, which aimed to encourage the implementation of public policies, carried out by a group of five autonomous researchers, from Brazil, Africa and North America, published in The International Journal of Health Planning and Management, entitled Drought, desertification and poverty: A geospatial analysis of snakebite envenoming in the Caatinga biome of Brazil  revealed that snakebites in the Brazilian Caatinga occur predominantly in low-income areas, with limited access to hospitals and medicines, as well as in rural areas of sub-Saharan Africa, considered neglected regions. The study compared public data on snakebites from the Brazilian Epidemiological Surveillance System (DATASUS), rainfall records, advanced desertification maps, pastures, and socioeconomic information from the 184 municipalities of Ceará between 2001 and 2017. During the investigation period, 8,945 snake accidents were recorded, most (93.8%) involving venomous snakes.

Another study recently published in the online scientific journal Plos One points out that, in most Brazilian municipalities where there is a higher risk of snake bites, the time demanded to obtain the antivenom can be fatal. The article “Geographical accessibility to the supply of antiophidic sera in Brazil: Timely access possibilities” provides information on the possibility of reaching health units that provide antivenom from the relationship between population distribution and travel time, considering that the ideal estimated time for the application would be up to two hours after the bite. The survey crossed population data from the Brazilian Institute of Geography and Statistics (IBGE) with information from the National Toxic-Pharmacological Information System (Sinitox/Icict/Fiocruz) and Sinan, in addition to using systems such as Google Maps and Google Street View, and even NASAs SRTM – Shuttle Radar Topography Mission.

Dr. Sharma further notes that the global burden of snakebite envenoming in animals was totally unknown prior to the study published in March. We have found a high incidence (42-202/100,000 inhabitants per year) and mortality (79-100%) in several animals, mostly birds, cattle, and goats. Since Nepal is a predominantly agricultural country, with 80% of its population depending on this activity for subsistence, animal losses increase and impacts the burden of snakebites on humans,, he signs.

In 2004, the American Society of Tropical Medicine and Hygiene (ASTMH) published the report “Impact of snake bites and determinants of fatal outcomes in southeastern Nepal” in which it highlighted that reliable data on snakebite morbidity and mortality were scarce due to lack of community surveys. Also according to the document, the existing snakebite reporting system in Nepal relies on hospital data that likely grossly underestimates both incidence and mortality, as shown elsewhere.

In many countries where snakebites are common, health systems often lack the infrastructure and resources to collect reliable statistical data about the problem. Assessing the true impact is further complicated by the fact that cases reported by clinics and hospitals to ministries of health often represent only a small part of the real problem, as many victims never reach health facilities. As seen, snakebites mainly affect people living in rural areas and in forests in relatively poorer regions, often not seen by health systems and also by public policies in general.

Low production of antidotes

A 2010 study estimated that only 2% of people bitten by poisonous snakes in sub-Saharan Africa had access to quality antidotes, and little has changed since then. In situations where data on snakebite envenomations are scarce, it is difficult to accurately determine the needs for antivenom. This leads national health authorities to underestimate these needs, with the consequent reduction in demand for antidote manufacturers and, in some cases, their withdrawal from the market.

Low demand has led several manufacturers to stop production and the price of has risen dramatically over the past 20 years, making treatment inaccessible to most people in need. Rising prices have further reduced demand, to the point that treatment has significantly decreased, or even disappeared, in some areas. The introduction of inappropriate, untested or even falsified antidotes in some markets has undermined overall confidence in treatment. Many believe that a collapse in the supply of antidotes in Africa and some Asian countries is imminent if strong and decisive action is not taken quickly.

Being predominantly a disease of the poor, the confrontation of snakebites at the global and regional level must be based on a philosophy of integration, cooperation and solidarity, far from the for-profit, nationalist and individualist philosophy that, unfortunately, often prevails in the global arena. Cooperation between countries and regions, including countries in the Global South, is of paramount importance, says Dr. Gutiérrez, citing as an example the Network of Public Antivenom Manufacturing Laboratories (RELAPA) that exists in Latin America, and the promotion of research networks and the integration of community initiatives that are being developed in many places. “Coordinated regional and global efforts should be promoted and strengthened, with the participation of as many stakeholders as possible, in order to reduce human suffering and despair caused by snakebites,” he advises.

In the opinion of Dr. Sharma, as the production of antivenom is driven by the market and it is limited, since snakebite occurs in the financially disadvantaged rural population, it is likely that pharma industries are not sufficiently motivated to invest in R&D and antivenom production. For him, the involvement of development and philanthropic organizations can probably change the scenario and there are indications in this line. All stakeholders must come forward to be the voice of the voiceless, i.e., the victims of snakebite.

For Dr. Bernarde, the lack of attention of governments is reflected in the lack of political representation of these populations and the pharmaceutical industry by often prioritizing diseases present in populations of richer countries, which enables greater profit from their investments in research. The ophidian accident is not a health problem that can be eradicated, it can only have several actions that can contribute to its control and better outcome of envenomation cases. To change this scenario, it is necessary to create awareness actions in these most vulnerable populations and implement measures that can facilitate victims access to quality treatment capable of reversing the clinical picture of envenomation, he recalls.

Example of public policy

Since the 20th century, Costa Rica has been making sustained efforts to prevent and control snakebites. The Clodomiro Picado Institute of the University of Costa Rica produces all the necessary antidotes to the country. In addition, the country has a robust public health system that provides antivenom and free medical treatment to all people victims of snakebites. The experience gained in recent decades is being projected regionally and globally to support other countries in Latin America and Sub-Saharan Africa in coping with this NTD. Dr. Gutiérrez explains that historically the country has faced the problem through an integrated and concerted public national strategy that involves the local production of antivenoms and their distribution at all levels of the health system, strengthening the public health system that has universal coverage, training of doctors and nursing professionals for the diagnosis and management of accidents and development of an active scientific and technological research agenda. Permanent prevention programs are also carried out in vulnerable groups, including indigenous communities, with the active involvement of local organizations. More recently, a new legislation was enacted in the country to offer compensation and rehabilitation support to rural workers affected by the sequelae of this disease. Thus, Costa Rica has built a strong platform to study, prevent and treat snakebite envenomation.

Another example comes from Nepal. According to Dr. Sharma, who is also a member of the who Working Group on Ophidic Accidents and is on the board of the Global Initiative on Ophidic Accidents, the government has always given priority to snakebite, being the first country in the region to provide free antivenom to victims since 1999. In addition, the Epidemiology and Disease Control section also conducts regular training for health professionals in snakebite management. “We have our own evidence-based National Guideline on snakebite management, which is usually done in collaboration with the WHO national office. However, Nepal do not produce antivenom and has to depends upon the antivenom produce in India. But most importantly, our field-based data can help develop intersectoral strategies on snakebite envenoming, including interactions in Nepal between Ministries of Health and Population, Agriculture and Livestock Development, Forests and Environment, and corresponding UN agencies (e.g., WHO, UNICEF, FAO, UNEP). Animal losses due to snakebite increase this burden in humans and require intersectoral actions by One Health,” he concludes.

Brazil as a reference in the production of antivenom sera

Before the creation of the antivenom in the country by Vital Brazil in 1901, the lethality of snake envenomations was 25%. This rate decreased over the years with the expansion of the production and distribution of antivenom in Brazil, currently with a lethality of approximately 0.4%. For Dr. Bernarde, even with aspects to be improved, such as the demand for serum being properly met and efficiently distributed to be sufficiently available both spatially and seasonally, we can say that Brazil is an example in dealing with ophidism. However, for the researcher, although Brazil is considered an example, there are still many aspects that can and need to be improved. Apparently the production of serum may not be enough to meet the national demand, or else, something is not being enough in relation to the distribution in hospital units, since it is common the lack of ampoules in certain locations throughout the year, he evaluates. The researcher also recalls that many communities in the Amazon do not have electricity and conditions to ideally mainten sera, which need to be properly refrigerated to be used. In such cases, the production of lyophilized serum could circumvent the problem. A working group of the Ministry of Health could reassess these aspects that can and should be improved so that the whole process, ranging from the production, availability and reach of the population, to the proper application, suggests.

The Butantan Institute is the largest producer and delivers 275 thousand vials of antivenom to the Ministry of Health annually for distribution to states and municipalities. Now, a partnership between the Institute and the Dr Heitor Vieira Dourado Tropical Medicine Foundantion, from the Amazonas State University (FMT/UEA) aims to increase access to treatment for Indigenous people, riverside dwellers, farmers, and other residents of remote areas of the Amazon. Through the partnership, 800 vials of serpent antivenom serum were donated to be used in units of low complexity, of these, antibotropic (pentavalent) and 100 antibotropic (pentavalent) and anti-laquetic, indicated against bites of venomous snakes that most protagonize accidents of the type in the Amazon Region. The place registers five times more accidents than in the rest of the country, but hospitals qualified for the application of antivenom are usually in urban areas, kilometers away from rural areas and forests.

Local and global challenge

Dr. Gutiérrez reinforces that because it is a “disease of the poor,” historically, and with few notable exceptions, the snakebite has not received the attention it deserves. For him, this is reflected in the low profile of this topic in the global research agendas, international pharmaceutical industry, and public health authorities. “Fortunately, this situation has begun to change in the last decade due to the joint efforts of many people and organizations around the world, who have advocated for greater attention to this disease. As a consequence of these initiatives, the WHO included snakebite envenoming in its list of NTDs in 2017, a resolution on the subject was adopted by the World Health Assembly in 2018, urging Member States to develop programs to reduce its impact, and a global strategy for prevention and control of snakebites was issued with the WHO in 2019. Thus, the negligence scenario is turning into a commitment scenario, although there is still a long way to meet this goal, concludes Dr. Gutiérrez.

Dr. Sharma agrees. For him, combined and coordinated efforts from all stakeholders are needed, as described by WHO as four pillars to achieve this goal: ensuring that safe and effective treatment is available and accessible to all; empowering national, local and regional communities for proactive measures, as well as improving community awareness; strengthening health systems to provide better results – here he highlights the inadequate training of physicians in the management of snakebites, leading to an ineffective workforce to deal with victims; and, finally, developing a strong global coalition of partners to build defense, mobilize resources, coordinate actions and ensure that the implementation of the roadmap is successful.

Adequate knowledge of the magnitude of the burden and the consequences that snake bites can lead to is essential for the adoption of appropriate prevention, detection and control measures. Finally, Dr. Sharma mentions the formulation of an appropriate set of interventions to improve access to health care (anti-ophidics, fans) and implement prevention activities (footwear, occupational analysis, promotion of motorcycle transport, etc.). Although it has remained neglected in the past, with the WHO resolution and the publication of the roadmap to implement strategies to prevent, reduce and control the burden of snakebite, the theme has led to new horizons, and I very much hopeful that the goal to reduce snakebite-related deaths to 50% will be achieved by 2030 concludes Dr. Sharma.

Dr. Bernarde points out another aspect that he considers of paramount importance: the notorious unpreparedness of a significant part of health professionals in dealing with cases of ophidic accidents, which probably reflects the lack of disciplines in specific undergraduate courses on venomous animals, as well as training courses for health professionals who are on the front line in emergency rooms – those who actually receive patients bitten by snakes. For him, the calls for research and extension actions in the area of Health should also include snakebites, since the WHO includes these in the list of neglected tropical diseases. “Simple measures can help a lot. A study published in 2017 in the Journal of Occupational Medicine and Toxicology entitled “Prevention of krait bites by sleeping above ground: preliminary results from an observational pilot study  showed that the simple donation of beds to residents in two villages with high cases of krait bites (snake that bites people mainly when they are sleeping on the floor) in the Kilinochchi district (Sri Lanka), provided a reduction in cases of envenomation by these snakes”, he exemplifies.

Snakes are in nature in various natural and anthropogenic habitats, playing an important role in ecosystems. It is up to the human being to find strategies to reduce the risks of snakebites and seek appropriate conditions that allow the best possible outcome in case of envenomation. These conditions involve, from the knowledge of the correct first aid conducts, vehicles that enable rapid displacement to hospital care, which must have sufficient infrastructure conditions, health professionals prepared to deal with ophidism and the antivenom available, concludes Dr. Bernarde.