The State-of-the-Art of the Humoral Memory Response to Snakebites: Insights from the Yanomami Population.

Snakebite envenomation (SBE)-induced immunity refers to individuals who have been previously bitten by a snake and developed a protective immune response against subsequent envenomations. The notion stems from observations of individuals, including in the indigenous population, who present only mild signs and symptoms after surviving multiple SBEs. Indeed, these observations have engendered scientific interest and prompted inquiries into the potential development of a protective immunity from exposure to snake toxins. This review explores the evidence of a protective immune response developing following SBE. Studies suggest that natural exposure to snake toxins can trigger protection from the severity of SBEs, mediated by specific antibodies. However, the evaluation of the immune memory response in SBE patients remains challenging. Further research is needed to elucidate the immune response dynamics and identify potential targets for therapeutic interventions. Furthermore, the estimation of the effect of previous exposures on SBE epidemiology in hyperendemic areas, such as in the indigenous villages of the Amazon region (e.g., the Yanomami population) is a matter of debate.

Multifaceted community health education programs as powerful tools to mitigate snakebite-induced deaths, disabilities, and socioeconomic burden.

Snakebite envenoming (SBE) predominantly affects rural impoverished communities that have limited access to immediate healthcare. These communities often hold numerous myths/misbeliefs about snakes and SBE. Moreover, healthcare professionals who practice in rural regions often work in unstable situations with limited medical infrastructure and therefore, lack sufficient knowledge/experience and confidence in the clinical management of SBE. Due to the lack of reliable statistics on the true burden of SBE, developing health policies for this condition by relevant authorities may be difficult. Hence, it is critical to improve awareness about SBE among rural communities, healthcare professionals and health authorities using robust multifaceted community health education approaches. Here, we describe the design, development, implementation, and impact of distinctive community health education approaches that we used in India and Brazil. A wide range of educational tools including information leaflets, posters, pocket guides, learning materials for healthcare professionals and short/long video documentaries were developed in local languages and used to engage with target communities through direct assemblies as well as mass/traditional and social media. Notably, we used diverse methods to determine the impact of our programs in improving awareness, treatment-seeking behaviour, and clinical practice. The people-centred approaches that we used were inclusive and highly impactful in instigating fundamental changes in the management of SBE among rural communities. The resources and approaches presented in this article can be easily adapted for wider use in other countries in order to collectively reduce SBE-induced deaths, disabilities and socioeconomic ramifications.

Envenomation by Micrurus hemprichii in Brazilian Amazonia: A report of three cases.

Herein, we report three new separate cases of human envenomations by Micrurus hemprichii for the Amazon, which is a biome where envenomations by Micrurus are seldom reported. Two women were bitten after stepping on the snakes and one man was bitten while handling the animal. All cases occurred in the peridomicile, in rural areas. The first case evolved mainly to local symptoms, but the patient was discharged before the identification of the snake and had to be called back for observation before being eventually discharged. In the second case, the patient presented transitory dyspnea and she was discharged after four days in hospital. In the third case, the patient showed only local symptoms, but he was about to receive unnecessary antivenom against coral snakes. Cases like these show the importance of educational problems regarding local venomous snakes in order to avoid bites and to provide the correct hospital treatment. For this, trained professionals in cases involving venomous animals are needed.

The severity of acute kidney injury correlates with plasma venom levels in Bothrops atrox envenomings.

The Brazilian Amazon has high rates of snakebite envenomings (SBEs), with ∼90% caused by Bothrops atrox. Envenomings by this species can trigger local and systemic effects, such as acute kidney injury (AKI). Our aim was to identify predictors of AKI in Bothrops SBEs in patients from Manaus, Western Brazilian Amazon. A total of 127 patients were enrolled, with a predominance of men between 16 and 45 years old from rural areas. Of the 127 patients, 38.6% developed AKI, with 61.2% presenting stage I, 34.7% presenting stage II and 4.1% presenting stage III severity. The age groups 0-10 years and ≥60 years presented a significantly higher frequency of AKI compared to the 11-40 years group. Moderate/severe edema in the affeccted limb was significantly associated with lower risk of AKI [p = 0.01; OR = 0.11 (95%CI 0.02-0.53)]. Nausea [p = 0.01; OR = 54.44 (95%CI = 3.26-909.27)] and high blood urea levels [p = 0.01; OR = 5.38 (95%CI = 2.12-13.66)] were risk factors for AKI. There was a significant positive correlation between circulating venom levels and the highest creatinine serum values during the hospital stay (p = 0.03) and with the difference between the maximum creatinine levels and the creatinine levels on admission (p = 0.02). A positive correlation between serum venom concentrations and creatinine levels suggests a direct or indirect dose-dependent participation of the venom toxins in the pathogenesis of AKI.

Case Report: Late-Onset Pneumonitis after Apoica pallida (Insecta: Hymenoptera) Sting with Anaphylactic Reaction in the Brazilian Amazon.

Hymenopteran venoms, inoculated during stings by ants, bees, and wasps, are the most frequent cause of an IgE-mediated systemic hypersensitivity reaction in adults, which is a key process in drastic manifestations of anaphylaxis. Respiratory involvement is usually caused by pulmonary edema but is rarely described as including interstitial pneumonitis or acute respiratory distress syndrome. Here, we describe a case of severe allergic reaction after a sting by Apoica pallens with late-onset pulmonary involvement, including signs of vasoplegia (pleural effusion) and interstitial pneumonitis with mild rhabdomyolysis. The presence of late onset of pulmonary involvement after a severe allergic reaction after a sting by A. pallens shows the importance of keeping a patient with severe reactions under medical care for a minimum of 5 days to avoid serious late complications outside the hospital environment.

Access to antivenoms in the developing world: A multidisciplinary analysis.

Access to safe, effective, quality-assured antivenom products that are tailored to endemic venomous snake species is a crucial component of recent coordinated efforts to reduce the global burden of snakebite envenoming. Multiple access barriers may affect the journey of antivenoms from manufacturers to the bedsides of patients. Our review describes the antivenom ecosystem at different levels and identifies solutions to overcome these challenges. At the global level, there is insufficient manufacturing output to meet clinical needs, notably for antivenoms intended for use in regions with a scarcity of producers. At national level, variable funding and deficient regulation of certain antivenom markets can lead to the procurement of substandard antivenom. This is particularly true when producers fail to seek registration of their products in the countries where they should be used, or where weak assessment frameworks allow registration without local clinical evaluation. Out-of-pocket expenses by snakebite victims are often the main source of financing antivenoms, which results in the underuse or under-dosing of antivenoms, and a preference for low-cost products regardless of efficacy. In resource-constrained rural areas, where the majority of victims are bitten, supply of antivenom in peripheral health facilities is often unreliable. Misconceptions about treatment of snakebite envenoming are common, further reducing demand for antivenom and exacerbating delays in reaching facilities equipped for antivenom use. Multifaceted interventions are needed to improve antivenom access in resource-limited settings. Particular attention should be paid to the comprehensive list of actions proposed within the WHO Strategy for Prevention and Control of Snakebite Envenoming.

Association of cfDNA levels and bothrops envenomation.

In the Amazon, around 90% of snakebites are caused by the Bothrops genus. Complications arising from Bothrops envenomations result from the inflammatory and coagulotoxic activities of the venom. The aim of this study was to investigate the potential of cell-free DNA (cfDNA) as a biomarker of severity in Bothrops snakebites. Patients were treated at the Fundação de Medicina Tropical Dr. Heitor Vieira Dourado (FMT-HVD), Manaus, in the Brazilian Amazon. cfDNA plasma levels were measured by amplifying the human telomerase reverse transcriptase (hTERT) sequence using quantitative RT-PCR. Median levels of cfDNA were compared between envenomed and healthy volunteers and among patients presenting different complications, such as renal failure, bleeding and infection. Of the 76 patients included, 82.9% were male, with a mean age of 32.8 years, and envenomations were mainly classified as severe (39.5%). ROC curve analysis showed a good accuracy of cfDNA levels (AUROC of 0.745) in envenomation diagnosis. A correlation analysis using laboratory variables showed positive correlation with lactate dehydrogenase (p = 0.033) and platelet count (p = 0.003). When cfDNA levels were compared with clinical complications, significant statistical differences were only found among individuals with mild and severe pain (p < 0.05). In summary, our results demonstrated that cfDNA levels are sufficiently accurate for discriminating between envenomed and non-envenomed patients, but are not able to distinguish different complications and the level of severity among envenomed patients. Thus, the role of cfDNA in the pathogenesis of the snakebite envenomations needs to be further investigated.

Clinical profile of confirmed scorpion stings in a referral center in Manaus, Western Brazilian Amazon.

Scorpion envenomations are a major public health problem in Brazil, and most medically important cases are attributable to the Tityus genus. The objective of this study is to describe the clinical and epidemiological aspects of a series of 151 cases of confirmed scorpion stings, which were treated at the hospitals of two cities in the Western Brazilian Amazon, between June 2014 and December 2019. This study shows that the genus Tityus was the most prevalent. Tityus (Atreus) metuendus (Pocock, 1897) was responsible for the greatest number of cases (68.2%), followed by Tityus (Archaeotityus) silvestris (Pocock, 1897) (14.6%). Most of the envenomations involved males (53.6%), and analysis showed a slight predominance in the group from 40 to 49 years (22.5%). The most affected body regions were feet (49.0%) and hands (31.8%). The time elapsed between the accident and medical care was ≤6 h in 92.1% of cases. Regarding clinical severity, classes I (80.8%) and II (15.9%) predominated. However, there were five (3.3%) class III cases; four for T. metuendus and one for T. silvestris. The most frequent local and systemic manifestations were, respectively, pain (84.1%), paresthesia (34.4%) and mild edema (25.8%), and nausea (9.3%) and myoclonia (8.6%). The clinical manifestations were similar among the patients stung by the different species of scorpions. There were no differences between the manifestations of envenomation caused by T. metuendus, T. silvestris and T. raquelae. For victims of T. apiacas, a higher frequency of piloerection and myoclonia was observed, and was described by the affected patients as a 'sensation of receiving an electric shock' throughout the body. No deaths were registered. The species of greatest epidemiological importance in Manaus is T. metuendus, a species that leads to clinical pictures that do not differ substantially from those observed in other Brazilian regions. T. apiacas causes neurological manifestations that differed from other Tityus species. Our findings suggest that the available antivenoms have little effectiveness when used in the treatment of envenomations by some Amazonian scorpions.

The relationship between clinics and the venom of the causative Amazon pit viper (Bothrops atrox).

Snake venoms are complex mixtures of proteins with toxic activities, with many distinct isoforms, affecting different physiological targets, comprised in a few protein families. It is currently accepted that this diversity in venom composition is an adaptive advantage for venom efficacy on a wide range of prey. However, on the other side, variability on isoforms expression has implications in the clinics of human victims of snakebites and in the efficacy of antivenoms. B. atrox snakes are responsible for most of the human accidents in Brazilian Amazon and the type and abundance of protein families on their venoms present individual variability. Thus, in this study we attempted to correlate the individual venom proteome of the snake brought to the hospital by the patient seeking for medical assistance with the clinical signs observed in the same patient. Individual variability was confirmed in venoms of the 14 snakes selected for the study. The abundance of each protein family was quite similar among the venom samples, while the isoforms composition was highly variable. Considering the protein families, the SVMP group presented the best correlation with bleeding disorders and edema. Considering individual isoforms, some isoforms of venom metalloproteinase (SVMP), C-type lectin-like toxins (CTL) and snake venom serine proteinases (SVSP) presented expression levels that with statistically significant positive correlation to signs and symptoms presented by the patients as bleeding disorders, edema, ecchymosis and blister formation. However, some unexpected data were also observed as the correlation between a CTL, CRISP or LAAO isoforms with blister formation, still to be confirmed with a larger number of samples. Although this is still a small number of patient samples, we were able to indicate that venom composition modulates clinical manifestations of snakebites, to confirm at the bedside the prominent role of SVMPs and to include new possible toxin candidates for the development of toxin inhibitors or to improve antivenom selectiveness, important actions for the next generation treatments of snakebites.

Snakebite envenomation in the Brazilian Amazon: a cost-of-illness study.

BACKGROUND: Snakebites account for significant morbidity and mortality. Their occurrence in the Brazilian Amazon warrants an analysis that will enable better understanding of their economic impact and thus contribute to their management and prevention. This study aimed to estimate the cost of snakebite envenomation in the Brazilian Amazon in 2015. METHODS: We conducted a cost-of-illness study of snakebite in the Brazilian Amazon in 2015 based on official surveillance data to estimate burden from a societal, patient and public health system perspective. Direct medical costs were estimated via a top-down approach. Loss of productivity was estimated by a human capital approach. RESULTS: The study included 11 503 cases and 56 deaths. The estimated cost to the health system was US$3.115.861,28. The estimated cost due to premature death caused by snakebite was US$3031 300.38. The cost attributed to the loss of productivity due to absence from work was US$1539 518.62. The estimated cost from the patient's perspective was US$268 914.18. Therefore the total cost of snakebite in the Brazilian Amazon was estimated to be almost than US$8 million in 2015. CONCLUSIONS: The economic burden of snakebite in Brazilian Amazon is notably high. Snakebites cause loss of productivity through inpatient treatment or deaths.

Coral snake bites in Brazilian Amazonia: Perpetrating species, epidemiology and clinical aspects.

Coral snakes constitute a relatively diverse and little known group of venomous snakes. So far, data for this kind of snakebite in the Amazon region are based only on case reports. This study takes advantage of novel data from the Brazilian Health Ministry database from 2010 to 2015 and presents a review of the cases reported in the literature regarding the Amazonian biome both from Brazil and nearby countries. Thirty-four cases reported in the database were used in the study, representing 0.05% of the snakebites in Brazilian Amazonia for that period. The incidence rate was 0.123 cases/100,000 inhabitants/year. The most affected group is that of working age men, suggesting occupational risk. Most of bites were on lower limbs. Pain, edema and paresthesia were the most common symptoms. Systemic symptoms not usually associated with coral snakes envenomings, such as coagulopathy and thrombocytopenia, have been reported in Amazonia. Five patients received less antivenom than indicated by the Health Ministry. Based on these results, we recommend the execution of educational programs to avoid such accidents and to teach both the general public and health professionals the correct treatment for the bites. We also suggest that the covering of Intensive Care Units in the region needs to be improved to avoid deaths.

Perspectives and recommendations towards evidence-based health care for scorpion sting envenoming in the Brazilian Amazon: A comprehensive review.

Although underreported across the Amazon region, scorpion stings are very prevalent in some areas and can be potentially life-threatening, especially in children. The most vulnerable populations are those living in locations far from the capitals, hence having limited access to the health system where the appropriate structure for the treatment of severe cases is found. An abundant and diverse fauna of scorpions is found in the region, but few studies have been conducted to decipher the clinical characteristics and therapeutic response of the available antivenoms in envenomings caused by the various species. Antivenom underdosage as well as delayed medical assistance are common among indigenous populations, resulting in poor outcome rates. An in depth understanding of the epidemiological, clinical and therapeutic aspects of scorpion sting envenomings in the Amazon is necessary to improve the outcome of these cases.

Rattlesnakes bites in the Brazilian Amazon: Clinical epidemiology, spatial distribution and ecological determinants.

Crotalus bites are considered a public health problem especially in Latin America. This study was performed to describe the epidemiology, spatial distribution and environmental determinants of Crotalus durissus bites in the Brazilian Amazon. Crotalus durissus envenomings official database included cases reported from 2010 to 2015. A total of 70,816 snakebites were recorded in the Amazon Region, 3058 (4.3%) cases being classified as crotalid, with a mean incidence rate of 11.1/100,000 inhabitants/year. The highest mean incidence rates were reported in Roraima, Tocantins and Maranhão. Area covered by water bodies, precipitation and soil humidity were negatively associated to rattlesnake encountering. Rattlesnake bites incidence was positively associated to tree canopy loss and altitude. In the Amazon, severe manifestations at admission, delayed medical assistance, lack of antivenom administration and ages ≥61 and 0-15 years were predictors of death in C. durissus snakebites. Spatial distribution of rattlesnake bites across the Brazilian Amazon showed higher incidence in areas of transition from the equatorial forest to the savanna, and in the savanna itself. Such results may aid focused policy-making in order to mitigate the burden, clinical complications and death as well as to manage Crotalus rattlesnake populations in the Brazilian Amazon.

Snakebites as cause of deaths in the Western Brazilian Amazon: Why and who dies? Deaths from snakebites in the Amazon.

Snake envenoming represents a major burden for public health worldwide. In the Amazon, the official number of cases and deaths detected is probably underestimated because of the difficulty riverine and indigenous populations have reaching health centers in order to receive medical assistance. Thus, integrated analysis of health information systems must be used in order to improve adequate health policies. The aim of this work is to describe a series of deaths and identify risk factors for lethality from snakebites in the state of Amazonas, Brazil. All deaths from snakebites reported to the Brazilian Notifiable Diseases Surveillance System (SINAN) and to the Mortality Information System (SIM; ICD10-10th revision, X.29), from 2007 to 2015, were included. Variables were assessed by blocks with distal (ecological variables), intermediate (demographics) and proximal (clinical variables) components to identify predictors of case fatality. A total of 127 deaths from snakebites were recorded, with 58 pairs found through linkage of the SINAN and SIM databases (45.7%), 37 (29.1%) deaths found only in SINAN and 32 (25.2%) found only in the SIM. Deaths occurred mostly in males (95 cases; 74.8%) living in rural areas (78.6%). The most affected age group was the ≥61 years old (36 cases; 28.4%). Snakebites were presumably due to Bothrops snakes in 68.5% of the cases and Lachesis in 29.5% based on clinico-epidemiological diagnosis. A proportion of 26.2% of the cases received treatment over 24 h after the bite ocurred. On admission, cases were mostly classified as severe (65.6%). Overall, 28 patients (22.0%). Deceased without any medical assistance Antivenom was given to 53.5%. In the multivariate analysis, a distance from Manaus >300 km [OR = 3.40 (95%CI = 1.99-5.79); (p < 0.001)]; age ≥61 years [OR = 4.31 (95%CI = 1.22-15.21); (p = 0.023)] and Indigenous status [OR = 5.47 (95%CI = 2.37-12.66); (p < 0.001)] were independently associated with case fatality from snakebites. Severe snakebites [OR = 16.24 (95%CI = 4.37-60.39); (p < 0.001)] and a lack of antivenom administration [OR = 4.21 (95%CI = 1.30-13.19); (p = 0.014)] were also independently associated with case fatality. Respiratory failure/dyspnea, systemic bleeding, sepsis and shock were recorded only among fatal cases. In conclusion, i) death from snakebites was underreported in the mortality surveillance system; ii) older age groups living in remote municipalities and indigenous peoples were the population groups most prone to death; iii) lack or underdosage of antivenom resulted in higher case fatality and iv) systemic bleeding, circulatory shock, sepsis and acute respiratory failure were strongly associated to fatal outcome.

Scorpion envenoming caused by Tityus cf. silvestris evolving with severe muscle spasms in the Brazilian Amazon.

Scorpion stings are a public health problem in the Brazilian Amazon. However, detailed clinical characterization with the proper animal identification is scarce. Here we report a confirmed case of envenoming by Tityus cf. silvestris in the Brazilian Amazon. The case evolved with generalized muscle spasms and was treated with antivenom and supportive therapy, requiring intensive care unit admission. The patient evolved favourably and was discharged after 9 days of hospitalization.