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Introduction: The deaths from and morbidities associated with snakebites - amputations, loss of function in the limb, visible scarring or tissue damage - have a vast economic, social, and psychological impact on indigenous communities in the Brazilian Amazon, especially children, and represent a real and pressing health crisis in this population. Snakebite clinical and research experts have therefore proposed expanding antivenom access from only hospitals to include the community health centers (CHC) located near and within indigenous communities. However, there are no studies examining the capacity of CHCs to store, administer, and manage antivenom treatment. In response to this gap, the research team calling for antivenom decentralization developed and validated an expert-based checklist outlining the minimum requirements for a CHC to provide antivenom., Methods: The objective of this study was thus to survey a sample of CHCs in indigenous territories and evaluate their capacity to provide antivenom treatment according to this accredited checklist. The checklist was administered to nurses and doctors from 16 CHCs, two per indigenous district in Amazonas/Roraima states., Results: Our results can be conceptualized into three central findings: 1) most CHCs have the capacity to provide antivenom treatment, 2) challenges to capacity are human resources and specialized items, and 3) antivenom decentralization is feasible and appropriate in indigenous communities., Conclusion: Decentralization would provide culturally and contextually appropriate care accessibility to a historically marginalized and underserved population of the Brazilian Amazon. Future studies should examine optimal resource allocation in indigenous territories and develop an implementation strategy in partnership with indigenous leaders. Beyond the indigenous population, the checklist utilized could be applied to community health centers treating the general population and/or adapted to other low-resource settings., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Acute kidney injury (AKI) is a critical systemic complication caused by Bothrops envenoming, a neglected health problem in the Brazilian Amazon. Understanding the underlying mechanisms leading to AKI is crucial for effectively mitigating the burden of this complication. This study aimed to characterize the urinary protein profile of Bothrops atrox snakebite victims who developed AKI. We analyzed three groups of samples collected on admission: healthy subjects (controls, n = 10), snakebite victims who developed AKI (AKI, n = 10), and those who did not evolve to AKI (No-AKI, n = 10). Using liquid-chromatography tandem mass spectrometry, we identified and quantified (label-free) 1190 proteins. A panel of 65 proteins was identified exclusively in the urine of snakebite victims, with 32 exclusives to the AKI condition. Proteins more abundant or exclusive in AKI's urine were associated with acute phase response, endopeptidase inhibition, complement cascade, and inflammation. Notable proteins include serotransferrin, SERPINA-1, alpha-1B-glycoprotein, and NHL repeat-containing protein 3. Furthermore, evaluating previously reported biomarkers candidates for AKI and renal injury, we found retinol-binding protein, beta-2-microglobulin, cystatin-C, and hepcidin to be significant in cases of AKI induced by Bothrops envenoming. This work sheds light on physiological disturbances caused by Bothrops envenoming, highlighting potential biological processes contributing to AKI. Such insights may aid in better understanding and managing this life-threatening complication., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Brasileiro-Martins et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Currently, antivenoms are the only specific treatment available for snakebite envenoming. In Brazil, over 30% of patients cannot access antivenom within its critical care window. Researchers have therefore proposed decentralizing to community health centers to decrease time-to-care and improve morbidity and mortality. Currently, there is no evidence-based method to evaluate the capacity of health units for antivenom treatment, nor what the absolute minimum supplies and staff are necessary for safe and effective antivenom administration and clinical management., Methods: This study utilized a modified-Delphi approach to develop and validate a checklist to evaluate the minimum requirements for health units to adequately treat snakebite envenoming in the Amazon region of Brazil. The modified-Delphi approach consisted of four rounds: 1) iterative development of preliminary checklist by expert steering committee; 2) controlled feedback on preliminary checklist via expert judge survey; 3) two-phase nominal group technique with new expert judges to resolve pending items; and 4) checklist finalization and closing criteria by expert steering committee. The measure of agreement selected for this study was percent agreement defined a priori as ≥75%., Results: A valid, reliable, and feasible checklist was developed. The development process highlighted three key findings: (1) the definition of community health centers and its list of essential items by expert judges is consistent with the Brazilian Ministry of Health, WHO snakebite strategic plan, and a general snakebite capacity guideline in India (internal validity), (2) the list of essential items for antivenom administration and clinical management is feasible and aligns with the literature regarding clinical care (reliability), and (3) engagement of local experts is critical to developing and implementing an antivenom decentralization strategy (feasibility)., Conclusion: This study joins an international set of evidence advocating for decentralization, adding value in its definition of essential care items; identification of training needs across the care continuum; and demonstration of the validity, reliability, and feasibility provided by engaging local experts. Specific to Brazil, further added value comes in the potential use of the checklist for health unit accreditation as well as its applications to logistics and resource distribution. Future research priorities should apply this checklist to health units in the Amazon region of Brazil to determine which community health centers are or could be capable of receiving antivenom and translate this expert-driven checklist and approach to snakebite care in other settings or other diseases in low-resource settings., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Serrão-Pinto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The indigenous populations of Brazil present poor health indicators and a disproportionate prevalence and case-fatality rate of neglected tropical diseases, including snakebite envenomations (SBEs). This study aims to estimate access to medical care for SBEs and analyze the barriers that prevent victims from accessing healthcare in indigenous communities in two health districts located in the Western Brazilian Amazon., Methodology/principal Findings: This cross-sectional study used semi-structured interviews to collect data from individuals who experienced SBEs in the Upper Rio Solimões and Upper Rio Negro indigenous health districts. Of the 187 participants, 164 (87.7%) reported that they had access to healthcare and received assistance in a hospital in the urban area of the municipalities. Frequency was 95.4% in the Upper Rio Solimões SIHD, and 69.6% in the Upper Rio Negro SIHD (P<0.0001). The study found that the availability of indigenous medicine as the only choice in the village was the main reason for not accessing healthcare (75%), followed by a lack of financial resources and means of transportation (28.1%). Four deaths were reported from SBEs, resulting in a case-fatality rate of 2.1%., Conclusions/significance: In the study areas, there are records of SBE patients who did not receive medical attention. Availability of pre-hospital emergency transport using motorboats, a greater number of hospitals and better navigability of the Solimões River and its tributaries would make access easier for indigenous people living in the region of the Upper Solimões River. The implementation of cross-cultural hospital care needs to be considered in order to reduce the resistance of indigenous populations in relation to seeking treatment for SBEs., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 de Farias et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Snakebite envenoming (SBE) is a neglected tropical disease capable of causing both significant disability and death. The burden of SBE is especially high in low- and middle-income countries. The aim of this study was to perform a geospatial analysis evaluating the association of sociodemographics and access to care indicators on moderate and severe cases of SBE in Brazil., Methods: We conducted an ecological, cross-sectional study of SBE in Brazil from 2014 to 2019 using the open access National System Identification of Notifiable Diseases (SINAN) database. We then collected a set of indicators from the Brazil Census of 2010 and performed a Principal Component Analysis to create variables related to health, economics, occupation, education, infrastructure, and access to care. Next, a descriptive and exploratory spatial analysis was conducted to evaluate the geospatial association of moderate and severe events. These variables related to events were evaluated using Geographically Weighted Poisson Regression. T-values were plotted in choropleth maps and considered statistically significant when values were <-1.96 or >+1.96., Results: We found that the North region had the highest number of SBE cases by population (47.83/100,000), death rates (0.18/100,000), moderate and severe rates (22.96/100,000), and proportion of cases that took more than three hours to reach healthcare assistance (44.11%). The Northeast and Midwest had the next poorest indicators. Life expectancy, young population structure, inequality, electricity, occupation, and more than three hours to reach healthcare were positively associated with greater cases of moderate and severe events, while income, illiteracy, sanitation, and access to care were negatively associated. The remaining indicators showed a positive association in some areas of the country and a negative association in other areas., Conclusion: Regional disparities in SBE incidence and rates of poor outcomes exist in Brazil, with the North region disproportionately affected. Multiple indicators were associated with rates of moderate and severe events, such as sociodemographic and health care indicators. Any approach to improving snakebite care must work to ensure the timeliness of antivenom administration., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Isaacson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Envenomation caused by venomous animals may trigger significant local complications such as pain, edema, localized hemorrhage, and tissue necrosis, in addition to complications such as dermonecrosis, myonecrosis, and even amputations. This systematic review aims to evaluate scientific evidence on therapies used to target local effects caused by envenomation. The PubMed, MEDLINE, and LILACS databases were used to perform a literature search on the topic. The review was based on studies that cited procedures performed on local injuries following envenomation with the aim of being an adjuvant therapeutic strategy. The literature regarding local treatments used following envenomation reports the use of several alternative methods and/or therapies. The venomous animals found in the search were snakes (82.05%), insects (2.56%), spiders (2.56%), scorpions (2.56%), and others (jellyfish, centipede, sea urchin-10.26%). In regard to the treatments, the use of tourniquets, corticosteroids, antihistamines, and cryotherapy is questionable, as well as the use of plants and oils. Low-intensity lasers stand out as a possible therapeutic tool for these injuries. Local complications can progress to serious conditions and may result in physical disabilities and sequelae. This study compiled information on adjuvant therapeutic measures and underscores the importance of more robust scientific evidence for recommendations that act on local effects together with the antivenom.

Background: In the Brazilian Amazon, snakebite envenomings (SBE) disproportionately affect indigenous peoples. Communication between indigenous and biomedical health sectors in regards to SBEs has never been explored in this region. This study aims to build an explanatory model (EM) of the indigenous healthcare domain for SBE patients from the perspective of the indigenous caregivers., Methodology/principal Findings: This is a qualitative study involving in-depth interviews of eight indigenous caregivers who are representatives of the Tikuna, Kokama and Kambeba ethnic groups, in the Alto Solimões River, western Brazilian Amazon. Data analysis was carried out via deductive thematic analysis. A framework was built containing the explanations based on three explanatory model (EM) components: etiology, course of sickness, and treatment. To indigenous caregivers, snakes are enemies and present conscience and intention. Snakebites have a natural or a supernatural cause, the last being more difficult to prevent and treat. Use of ayahuasca tea is a strategy used by some caregivers to identify the underlying cause of the SBE. Severe or lethal SBEs are understood as having been triggered by sorcery. Treatment is characterized by four components: i) immediate self-care; ii) first care in the village, mostly including tobacco smoking, chants and prayers, combined with the intake of animal bile and emetic plants; iii) a stay in a hospital, to receive antivenom and other treatments; iv) care in the village after hospital discharge, which is a phase of re-establishment of well-being and reintroduction into social life, using tobacco smoking, massages and compresses to the affected limb, and teas of bitter plants. Dietary taboos and behavioral interdictions (avoiding contact with menstruating and pregnant women) prevent complications, relapses, and death, and must be performed up to three months after the snakebite. Caregivers are in favor of antivenom treatment in indigenous areas., Conclusions/significance: There is a potential for articulation between different healthcare sectors to improve the management of SBEs in the Amazon region, and the aim is to decentralize antivenom treatment so that it occurs in indigenous health centers with the active participation of the indigenous caregivers., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 de Farias et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Neglected tropical diseases (NTDs) disproportionately affect populations living in resource-limited settings. In the Amazon basin, substantial numbers of NTDs are zoonotic, transmitted by vertebrate (dogs, bats, snakes) and invertebrate species (sand flies and triatomine insects). However, no dedicated consortia exist to find commonalities in the risk factors for or mitigations against bite-associated NTDs such as rabies, snake envenoming, Chagas disease and leishmaniasis in the region. The rapid expansion of COVID-19 has further reduced resources for NTDs, exacerbated health inequality and reiterated the need to raise awareness of NTDs related to bites., Methods: The nine countries that make up the Amazon basin have been considered (Bolivia, Brazil, Colombia, Ecuador, French Guiana, Guyana, Peru, Surinam and Venezuela) in the formation of a new network., Results: The Amazonian Tropical Bites Research Initiative (ATBRI) has been created, with the aim of creating transdisciplinary solutions to the problem of animal bites leading to disease in Amazonian communities. The ATBRI seeks to unify the currently disjointed approach to the control of bite-related neglected zoonoses across Latin America., Conclusions: The coordination of different sectors and inclusion of all stakeholders will advance this field and generate evidence for policy-making, promoting governance and linkage across a One Health arena., (© The Author(s) 2022. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

Snakebite envenoming is currently considered a neglected tropical disease, which affects over 5 million people worldwide, and causes almost 150 000 deaths every year, as well as severe injuries, amputations and other sequelae. Snakebite envenoming in children, although proportionally less frequent, is generally more severe, and represents an important challenge for pediatric medicine, since they often result in worse outcomes. In Brazil, given its ecological, geographic and socioeconomic characteristics, snakebites are considered an important health problem, presenting approximately 30 000 victims per year, approximately 15% of them in children. Even with low snakebite incidence, children tend to have higher snakebite severity and complications due to the small body mass and same venom volume inoculated in comparison to adults, even though, due to the lack of epidemiological information about pediatric snakebites and induced injuries, it is difficult to measure the treatment effectiveness, outcomes and quality of emergency medical services for snakebites in children. In this review, we report how Brazilian children are affected by snakebites, describing the characteristics of this affected population, clinical aspects, management, outcomes and main challenges., (© The Author(s) [2023]. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Snakebite envenomations (SBEs) in pregnant women can result in adverse maternal or neonatal effects, such as abortion, placental abruption, preterm labor, fetal malformations, and maternal, fetal or neonatal deaths. Despite the high incidence of SBEs in the Brazilian Amazon, there is no literature on the impact of SBEs on pregnancy outcomes. The objective of this study was to describe clinical epidemiology and outcomes associated with SBEs in women of childbearing age and pregnant women in the state of Amazonas, Western Brazilian Amazon, from 2007 to 2021. Information on the population was obtained from the Reporting Information System (SINAN), Mortality Information System (SIM) and Live Birth Information System (SINASC) for the period from 2007 to 2021. A total of 36,786 SBEs were reported, of which 3,297 (9%) involved women of childbearing age, and 274 (8.3%) involved pregnant women. Severity (7.9% in pregnant versus 8.7% in non-pregnant women) (P = 0.87) and case-fatality (0.4% in pregnant versus 0.3% in non-pregnant women) rates were similar between groups (P = 0.76). Pregnant women who suffered snakebites were at higher risk for fetal death (OR: 2.17, 95%CI: 1.74-2.67) and neonatal death (OR = 2.79, 95%CI: 2.26-3.40). This study had major limitations related to the completeness of the information on the pregnancy outcomes. Although SBE incidence in pregnant women is low in the Brazilian Amazon, SBEs increased the risk of fetal and neonatal deaths., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Nascimento et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Snakebite envenoming (SBE) is a neglected tropical disease with significant global morbidity and mortality. Even when antivenom is available in low-resource areas, health workers do not receive adequate training to manage SBEs. This study aims to develop and validate a clinical practice guideline (CPG) for SBE management across Brazil. A panel of expert judges with academic and/or technical expertise in SBE management performed content validation. The content validity index (CVI) score was 90% for CPG objectives, 89% for structure and presentation and 92% for relevance and classified the CPG as valid. A semantic validation was performed by analyzing focus group discussions with doctors and nurses from three municipalities of the Brazilian Amazon, after a 5-day meeting during which the CPG was presented. Two central themes emerged: knowledge acquired during the meeting and recommendations for improving the CPG. Based on these results, the CPG was revised into a final version. This study presents the successful development and validation process of a CPG for SBE management, which is targeted to a specific low-resource, high-burden setting. This development and validation process can be adapted to other settings and/or other neglected tropical diseases.

Instituto Butantan (São Paulo, Brazil) and Instituto Clodomiro Picado (San José, Costa Rica) are public institutions devoted to scientific and technological research, production of antivenoms and other immunobiologicals, and a variety of public health interventions aimed at confronting the problem of snakebite envenoming in their countries and elsewhere. In the context of the 120th anniversary of Instituto Butantan, this work describes the historical developments in the relationship between these institutions, which has evolved into a solid cooperation platform in science, technology, and public health. The relationship between Instituto Butantan and Costa Rica started early in the 20th century, with the provision of Brazilian antivenoms to Costa Rica through the coordination of Instituto Butantan and the health system of Costa Rica, with the leadership of Clodomiro Picado Twight. After the decade of 1980, a prolific collaborative network has been established between Instituto Butantan and Instituto Clodomiro Picado (founded in 1970) in the areas of scientific and technological research in pharmacology, biochemistry, experimental pathology, immunology, and public health, as well as in antivenom development, production, preclinical evaluation, and quality control. In addition, both institutions have played a key role in the integration of regional efforts in Latin America to create a network of public institutions devoted to antivenom production and quality control, in close coordination with the Pan American Health Organization (PAHO). This long-standing partnership is an example of a highly productive south-south cooperation under a frame of solidarity and public well-being., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Access to antivenoms is not guarranteed for vulnerable populations that inhabit remote areas in the Amazon. The study of therapeutic itineraries (TI) for treatment of snakebites would support strategies to provide timely access to users. A TI is the set of processes by which individuals adhere to certain forms of treatment, and includes the path traveled in the search for healthcare, and practices to solve their health problems. This study aims to describe TIs of snakebite patients in the Brazilian Amazon. This study was carried out at the Fundação de Medicina Tropical Doutor Heitor Vieira Dourado, in Manaus, state of Amazonas, Brazil. The itinerary from the moment of the bite to the patient's admission to the reference unit was analyzed. Sample size was defined by saturation. After an exploratory survey to collect epidemiological variables, in-depth interviews were conducted following a semi-structured guide. Patients originated from rural areas of 11 different municipalities, including ones located >500 kilometers from Manaus. A great fragmentation was observed in the itineraries, marked by several changes of means of transport along the route. Four themes emerged from the analysis: exposure to snakebite during day-to-day activities, use of traditional therapeutic practices, and personal perception of the severity, as well as the route taken and its contingencies. Access to healthcare requires considerable effort on the part of snakebite patients. Major barriers were identified, such as the low number of hospitals that offer antivenom treatment, poor access to healthcare due to long distances and geographic barriers, low acceptability of healthcare offered in countryside, lack of use of personal protective equipment, common use of ineffective or deleterious self-care practices, late recognition of serious clinical signs and resistance to seeking medical assistance. Health education, promotion of immediate transport to health centers and decentralization of antivenom from reference hospitals to community healthcare centers in the Brazilian Amazon are more effective strategies that would to maximize access to antivenom treatment., Competing Interests: The authors have declared that no competing interests exist.

Snakebites are more frequent in the Brazilian Amazon than in other parts of Brazil, representing a high cost for the health system since antivenoms are only available through medical prescription from central municipal hospitals in most cases. The need for a cold chain and physicians usually restricts access to the only effective treatment of a snakebite, the antivenom. The complex topography of the rivers contributes to delays in treatment, and consequently increases the risk of severe complications, chronic sequelae and death. Thus, decentralization of antivenom treatment to primary healthcare facilities in the interior would increase access by indigenous population groups to proper healthcare. To standardize and evaluate the decentralization to low complexity indigenous healthcare units, we suggest the (i) development and validation of standardized operational procedures, (ii) training of professionals in the validated protocol in a referral health unit, (iii) implementation of the protocol in an indigenous healthcare unit, (iv) assessment of perceptions towards and acceptability of the protocol, and (v) estimation of the impact of the protocol's implementation. We expect that antivenom decentralization would shorten the time between diagnosis and treatment and, as such, improve the prognosis of snakebites. As health cosmology among indigenous populations has an important role in maintaining their way of life, the introduction of a new therapeutic strategy to their customs must take into account the beliefs of these peoples. Thus, antivenom administration would be inserted as a crucial therapeutic tool in a world of diverse social, natural and supernatural representations. The information presented here also serves as a basis to advocate for support and promotion of health policy initiatives focused on evidence-based care in snakebite management.

Snake 'dry bites' are characterized by the absence of venom being injected into the victim during a snakebite incident. The dry bite mechanism and diagnosis are quite complex, and the lack of envenoming symptoms in these cases may be misinterpreted as a miraculous treatment or as proof that the bite from the perpetrating snake species is rather harmless. The circumstances of dry bites and their clinical diagnosis are not well-explored in the literature, which may lead to ambiguity amongst treating personnel about whether antivenom is indicated or not. Here, the epidemiology and recorded history of dry bites are reviewed, and the clinical knowledge on the dry bite phenomenon is presented and discussed. Finally, this review proposes a diagnostic and therapeutic protocol to assist medical care after snake dry bites, aiming to improve patient outcomes.

Introduction: Snake venom composition shows significant inter- and intra-species variation. In the case of the viperid species Bothrops atrox , responsible for the majority of snakebites in the Amazon region, geographical and ontogenetic variables affect venom composition, with ecological and medical implications. Previous studies had shown that venom from neonate and juvenile Bothrops specimens have a higher in vitro coagulant activity. The aim of this investigation was to assess the association of clinical outcomes, such as venom-induced coagulopathy and local complications, with B. atrox ontogenetic variables. Methods: This study explored the relationship between some clinical parameters in patients suffering envenomations by B. atrox in the Amazon and several morphometric parameters of the snake specimens causing the bites. Results: There were 248 specimens confirmed as agents of envenomation, mostly female snakes (70.5%) and classified as juveniles (62.7%). Patients bitten by neonates compared to adult snakes [OR = 2.70 (95%CI 1.15-6.37); p  = .021] and by snakes with white tail tip [OR = 1.98 (95%CI 1.15-3.41); p  = .013] were more likely to develop coagulopathy. Time from patient admission to the unclottable blood reversion was not affected by the snake gender ( p  = .214) or age ( p  = .254). Patients bitten by neonate ( p  = .024) or juvenile snakes ( p  < .0001) presented a lower frequency of moderate to severe edema, as compared to those bitten by adult snakes. In agreement with experimental observations, patients bitten by neonates and by snakes with a white tail tip were more likely to develop coagulopathy than those bitten by adult snakes. In contrast, envenomations by adult snakes were associated with a higher incidence of severe local edema. Conclusion: Despite these variations, no difference was observed in the time needed to recover blood clotting in these patients after Bothrops antivenom administration.

Introduction: Bothrops atrox snakebites are a major public health problem in the Amazon region and also cause hemostatic disorders. In this study, we assessed the recovery from hemostatic disorders in Bothrops snakebite patients after being given antivenom therapy. Methods: This is a prospective study of Bothrops snakebite patients ( n  = 100) treated at the Fundação de Medicina Tropical Dr. Heitor Vieira Dourado , Manaus, Brazilian Amazon, between January 2016 and December 2017. Blood samples were taken for the measurement of venom concentrations, platelets, clotting time and factors of patients on admission, 12, 24 and 48 h after antivenom therapy, and taken again on discharge. The presence of systemic bleeding was recorded during the follow-up. Results: On admission, systemic bleeding was observed in 14% of the patients. Thrombocytopenia was noted in 10% of the patients. A total of 54% of the patients presented unclottable blood with low levels of fibrinogen and alpha 2-antiplasmin, and high levels of fibrin/fibrinogen degradation product (FDP) and D-dimers. Unclottable blood and systemic bleeding were overcome in most patients 12 h after the antivenom therapy. Three patients developed systemic bleeding 48 h after antivenom therapy. Levels of fibrinogen and alpha 2-antiplasmin, FDP and D-dimer returned to normal around 48 h after the treatment or on discharge. The frequency of thrombocytopenia with high mean platelet volume increased in the first 24 h after antivenom therapy, and decreased on discharge. Bothrops venom levels in patients decreased 12 h after antivenom therapy and were not correlated with coagulation and fibrinolytic parameters. There were no deaths. Conclusion: Laboratorial parameters of coagulopathy returned to normal values within 48 h after the antivenom therapy until discharge. A few patients still presented bleeding signs within 48 h after beginning antivenom therapy. However, the Brazilian antivenom was able to overcome the hemostatic disorders in these cases of envenomation.

Objectives: Although more than 1.8 million people survive snakebite envenomation each year, their recovery is understudied. Obtaining long-term follow-up is challenging in both high- and low-resource settings. The Patient-Specific Functional Scale (PSFS) is an easily administered, well-accepted patient-reported outcome that is validated for assessing limb recovery from snakebite envenomation. We studied whether the PSFS is valid and reliable when administered by telephone., Methods: This is a secondary analysis of data from a randomized clinical trial. We analyzed the results of PSFS collected in-person on days 3, 7, 14, 21, and 28 and by telephone on days 10, 17, and 24. We assessed the following scale psychometric properties: (a) content validity (ceiling and floor effects), (b) internal structure and consistency (Cronbach's alpha), and (c) temporal and external validity using Intraclass Correlation Coefficient (ICC). Temporal stability was assessed using Spearman's correlation coefficient and agreement between adjacent in-person and telephonic assessments with Cohen's kappa. Bland Altman analysis was used to assess differential bias in low and high score results., Results: Data from 74 patients were available for analysis. Floor effects were seen in the early post-injury time points (median: 3 (IQR: 0, 5) at 3 days post-enrollment) and ceiling effects in the late time points (median: 9 (IQR: 8, 10). Internal consistency was good to excellent with both in-person (Cronbach α: 0.91 (95%CI 0.88, 0.95)) and telephone administration (0.81 (0.73, 0.89). Temporal stability was also good (ICC: 0.83 (0.72, 0.89) in-person, 0.80 (0.68, 0.88) telephone). A strong linear correlation was found between in-person and telephone administration (Spearman's ρ: 0.83 (CI: 0.78, 0.84), consistency was assessed as excellent (Cohen's κ 0.81 (CI: 0.78, 0.84), and Bland Altman analysis showed no systematic bias., Conclusions: Telephone administration of the PSFS provides valid, reliable, and consistent data for the assessment of recovery from snakebite envenomation., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: Dr. Rose reports speakers bureau fees from BTG International Inc outside the submitted work. Dr. Greene reports receiving consulting fees and honoraria from BTGInternational Inc outside the submitted work. Drs. Gerardo, Charlton, Mullins, Lavonas and Kleinschmidt and Ms. Anderson report receiving prior study-related grants from BTG International Inc.

Introduction: The common lancehead snakes ( Bothrops atrox) are responsible for up to 90% of snakebites in the Amazon, especially in remote areas. The prevalence of microhematuria is similar to that of coagulopathy in B. atrox envenomation in the Amazon. Thus, this study aimed to assess the reliability of microhematuria as an inexpensive and simple alternative to detect snake-induced consumption coagulopathy. Methods: We analyzed samples from patients with confirmed B. atrox envenomation in terms of plasma fibrinogen and microhematuria (>3 red blood cells per high power field) in order to access the reliability of microhematuria to detect snakebite-induced coagulopathy, within 12 hours from admission. Results: A total of 186 patients were recruited. From the total, 85.5% of patients had hypofibrinogenemia and only about 50% ( n  = 94) had a microscopic examination of urine within 12 hours where microhematuria was present in 39 (41.5%). Diagnostic performance showed 38.6% sensitivity and 36.4% specificity (cutpoint 200 mg/dL). No clear association was seen between microhematuria and hypofibrinogenemia ( r : -0.10; p: .34). Conclusion: In this study, microhematuria presented poor diagnostic performance to detect coagulopathy. Further studies are necessary to screen inexpensive and simple alternative diagnostic tools.

Competing Interests: Dr Bernadette Abela-Ridder is an employee of the World Health Organization. Dr David Williams is engaged as a consultant to the World Health Organization. The majority of authors (excepting Dr Abela-Ridder, Dr Ainsworth, Mr Bulfone and Ms Nickerson) are members of the WHO Snakebite Envenoming Working Group. The authors have declared that no other competing interests exist.

A plan to achieve self-sufficiency in manufacturing biologicals for public health has been structured for the last 40 years in Brazil, in the context of a reform in the health system. Industrial plants of the national public laboratories have been modernized, and a program for reducing morbidity and mortality of venomous snakebite has been created, as part of the National Epidemiological Surveillance System. The epidemiological data are essential to plan for the antivenom production of 400,000 vials of snake antivenoms per year, and the acquisition by the Ministry of Health, which is the exclusive purchaser in the country. Distribution is decentralized to reach hospitals in almost 3000 municipalities, and to provide free of charge antivenom treatment. The National Sanitary Surveillance Agency organized the regulatory environment to implement rules and supervise compliance of GMP procedures, elevating the quality of the biologicals that are produced, as well as reducing the costs in production. Despite all the advances in the health system, antivenom availability and accessibility is not uniform in regards to the most vulnerable parts of the populations, which inhabit remote areas in the Brazilian Amazon region. Better logistics and transportation of liquid form antivenoms is an issue to be addressed and realistic and comprehensive health programs for indigenous groups should be effectively structured, in order to reduce the high morbidity and mortality rates associated with snakebite envenoming., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Acute Kidney Injury (AKI) is the main systemic complication and cause of death in viperid envenomation. Although there are hypotheses for the development of AKI, the mechanisms involved are still not established. The aim of this study was to evaluate the clinical-laboratorial-epidemiological factors associated with AKI in victims of Bothrops sp envenomation. This is an observational study carried out at the Fundação de Medicina Tropical Dr. Heitor Vieira Dourado. AKI was defined according to the guidelines of the Acute Kidney Injury Network (AKIN). Among the 186 patients evaluated, AKI was observed in 24 (12.9%) after 48 hours of admission. Stage I was present in 17 (70.8%) patients, II in 3 (12.5%) and III in 4 (16.7%). Epidemiological characterization showed predominance of men, occurrence in rural areas, aged between 16-60 years, feet as the most affected anatomical region, and time to medical assistance less than 3 hours. Hypertension and diabetes were the comorbidities identified. Most of the accidents were classified as moderate, and clinical manifestations included severe pain, mild edema, local bleeding and headache. Laboratory results showed blood uncoagulability, hypofibrinogenemia, leukocytosis, increase of creatine kinase, and high lactate dehydrogenase levels. Multivariate analysis showed an association with high LDH levels [AOR = 1.01 (95% CI = 1.01-1.01, p<0.002)], local bleeding [AOR = 0.13 (95%CI = 0.027-0.59, p<0.009)], and the presence of comorbidities [AOR = 60.96 (95%CI = 9.69-383.30; p<0.000)]. Herein, laboratory markers such as high LDH levels along with local bleeding and comorbidities may aid in the diagnosis of AKI., Competing Interests: The authors have declared that no competing interests exist.

Snake envenomation is a major public health problem in Brazil. Systemic complications that may arise from snakebites are mainly related to coagulopathy. The Lee-White clotting time (LWCT) is a simple and inexpensive test and available even in remote health facilities. However, the diagnostic value of such test needs to be evaluated to accurately diagnose coagulopathy in the clinical practice. This study aimed to assess the reliability of the LWCT performed in hospital routine to diagnose venom-induced coagulopathy. We studied 186 patients admitted at the Tropical Medicine Foundation Dr. Heitor Vieira Dourado in Manaus, Amazonas, Brazil, with Bothrops envenomation diagnosis. At admission, blood samples were collected for performing LWCT and the concentration of fibrinogen. Sensitivity, specificity, positive predictive value, negative predictive value, likelihood ratios, diagnostic odds ratio, and accuracy were calculated with 95% confidence intervals. From the total, 85.5% had hypofibrinogenemia. The sensitivity of the LWCT to the diagnosis of hypofibrinogenemia was 78.0% and the specificity 40.7%. The accuracy of the test was 72.6%, and patients with a prolonged LWCT had 2.4 higher odds of developing hypofibrinogenemia. In addition, the LWCT was also compared with venom antigen levels and systemic hemorrhage. The LWCT showed moderate sensitivity to detect consumption coagulopathy and constitutes a valuable tool for the diagnosis of Bothrops snake envenomation and indication of antivenom therapy.

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., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Bothrops atrox is the snake responsible for the majority of snakebites in the Brazilian Amazon. Patients generally evolve to local manifestations such as edema, pain and ecchymoses. Systemic effects of B. atrox venom are usually restricted to blood incoagulability and spontaneous bleeding. However, in a few cases, bleeding in the central nervous system may occur, which can lead to sequels and deaths. Here, we report a case of a 59 year-old woman who presented edema, pain and ecchymoses on the right foot, headache, nausea, diarrhea, hypertension and blood incoagulability after the bite by Bothrops snake in the Brazilian Amazon. This case evolved with stroke resulting in death despite the antivenom and conservative therapy employed. In addition, we were able to identify the presence of venom in the patient's brain tissue after death. Direct action of toxins present in the snake's venom in the induction of systemic hemorrhage allied to blood incoagulability and hypertension presented by the patient could be involved in the mechanism of stroke in this case., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Secondary bacterial infections from snakebites contribute to the high complication rates that can lead to permanent function loss and disabilities. Although common in endemic areas, routine empirical prophylactic use of antibiotics aiming to prevent secondary infection lacks a clearly defined policy. The aim of this work was to estimate the efficacy of amoxicillin clavulanate for reducing the secondary infection incidence in patients bitten by Bothrops snakes, and, secondarily, identify risk factors for secondary infections from snakebites in the Western Brazilian Amazon., Methods and Findings: This was an open-label, two-arm individually randomized superiority trial to prevent secondary infection from Bothrops snakebites. The antibiotic chosen for this clinical trial was oral amoxicillin clavulanate per seven days compared to no intervention. A total of 345 patients were assessed for eligibility in the study period. From this total, 187 accomplished the inclusion criteria and were randomized, 93 in the interventional group and 94 in the untreated control group. All randomized participants completed the 7 days follow-up period. Enzyme immunoassay confirmed Bothrops envenoming diagnosis in all participants. Primary outcome was defined as secondary infection (abscess and/or cellulitis) until day 7 after admission. Secondary infection incidence until 7 days after admission was 35.5% in the intervention group and 44.1% in the control group [RR = 0.80 (95%CI = 0.56 to 1.15; p = 0.235)]. Survival analysis demonstrated that the time from patient admission to the onset of secondary infection was not different between amoxicillin clavulanate treated and control group (Log-rank = 2.23; p = 0.789).Secondary infections incidence in 7 days of follow-up was independently associated to fibrinogen >400 mg/dL [AOR = 4.78 (95%CI = 2.17 to 10.55; p<0.001)], alanine transaminase >44 IU/L [AOR = 2.52 (95%CI = 1.06 to 5.98; p = 0.037)], C-reactive protein >6.5 mg/L [AOR = 2.98 (95%CI = 1.40 to 6.35; p = 0.005)], moderate pain [AOR = 24.30 (95%CI = 4.69 to 125.84; p<0.001)] and moderate snakebites [AOR = 2.43 (95%CI = 1.07 to 5.50; p = 0.034)]., Conclusions/significance: Preemptive amoxicillin clavulanate was not effective for preventing secondary infections from Bothrops snakebites. Laboratorial markers, such as high fibrinogen, alanine transaminase and C-reactive protein levels, and severity clinical grading of snakebites, may help to accurately diagnose secondary infections., Trial Registration: Brazilian Clinical Trials Registry (ReBec): RBR-3h33wy; UTN Number: U1111-1169-1005.

Snakebite envenoming is a neglected public health challenge of compelling importance in many regions of the world, particularly sub-Saharan Africa, Asia, Latin America and Papua-New Guinea. Addressing the problem of snakebite effectively demands an integrated multifocal approach, targeting complex problems and involving many participants. It must comprise: (a) Acquisition of reliable information on the incidence and mortality attributable to snakebite envenoming, and the number of people left with permanent sequelae. (b) Improvements in production of effective and safe antivenoms, through strategies aimed at strengthening the technological capacity of antivenom manufacturing laboratories. (c) Increasing the capacity of low-income countries to produce specific immunogens(snake venoms) locally, and to perform their own quality control of antivenoms. (d) Commitments from regional producers to manufacture antivenoms for countries where antivenom production is not currently feasible. (e) Implementation of financial initiatives guaranteeing the acquisition of adequate volumes of antivenom at affordable prices in low-income countries. (f) Performance of collaborative studies on the safety and effectiveness of antivenoms assessed preclinically and by properly designed clinical trials. (g) Development of antivenom distribution programmes tailored to the real needs and epidemiological situations of rural areas in each country. (h) Permanent training programmes for health staff, particularly in rural areas where snakebites are frequent.(i) Implementation of programmes to support those people whose snakebites resulted in chronic disabilities. (j) Preventive and educational programmes at the community level, with the active involvement of local organizations and employing modern methods of health promotion. Such an integrated approach, currently being fostered by the Global Snake Bite Initiative of the International Society on Toxinology and by the World Health Organization, will help to alleviate the enormous burden of human suffering inflicted by snakebite envenoming., (Copyright © 2009 Elsevier Ltd. All rights reserved.)

Two cases of proven coral snake bites were reported in Belém, Pará State, Brazil. The first case was a severe one caused by Micrurus surinamensis. The patient required mechanical ventilation due to acute respiratory failure. The second case showed just mild signs of envenomation caused by Micrurus filiformis. Both patients received specific Micrurus antivenom and were discharged without further complications. Coral snake bites are scarcely reported in the Amazon region and there is a broad spectrum of clinical manifestations, varying from extremely mild to those which may rapidly lead to death if the patient is not treated as soon as possible.

The issues of antivenom stability and distribution, and the training of health staff in the correct use of antivenoms in Latin America were discussed in a workshop held at Instituto Clodomiro Picado, Costa Rica, in September 16-19, 2008, under the auspices of the program CYTED. Participants from public antivenom production laboratories of the region, together with representatives of the Ministries of Health, from Argentina, Paraguay, Brazil, Bolivia, Perú, Ecuador, Colombia, Venezuela, Panamá, Costa Rica and Nicaragua participated in the event. Technical advances in the study of antivenom stability and in the design of novel formulations aimed at generating products of higher stability were presented. In addition, antivenom acquisition and distribution systems in every country were presented and discussed, together with novel tools that could be useful for improving antivenom distribution, such as the software SIGEpi, developed by the Pan American Health Organization. The issue of the cold chain, as well as the most frequent causes of misuse of antivenoms in the region, were also analyzed. Finally, the experiences of training programs for health staff on the correct use of antivenoms in snakebite envenomation treatment in Latin America were presented. It was concluded that, in addition to the fostering of antivenom production and quality control, renewed efforts should be implemented at improving the stability, distribution and correct use of antivenoms in the region.

The presence of human heterophilic antibodies against horse immunoglobulins (HHA-HI) was determined by ELISA in sera from healthy volunteers and from patients who received equine antivenom for therapy of snake bite envenoming. These patients were selected from two independent clinical studies: one in Colombia in which patients received antivenom constituted by whole IgG (n=25); and the other in Brazil where an antivenom constituted by F(ab')(2) fragments was administered (n=31). Results show that healthy volunteers have antibodies, mainly of the IgG class, able to react with whole equine IgG. Additionally, patients have IgG antibodies that react both with whole equine IgG and F(ab')(2) fragments. In both clinical studies, no significant differences were observed in the HHA-HI titres between the patients who presented early adverse (anaphylactoid) reactions and those who did not develop them. In addition, no variation in titre was observed in samples collected before and after antivenom administration. These results do not support the hypothesis that the incidence of early adverse reactions to antivenom administration correlates with the titre of HHA-HI in the serum of patients. Nevertheless, participation of these antibodies as part of a multifactorial pathogenic mechanism associated with these reactions cannot be ruled out.

Complete blood counts are used frequently by physicians to assess and manage the development of complications of diseases. We studied 100 patients bitten by Bothrops jararaca snakes, and correlated their haematological values with the severity of envenoming and the development of complications. Patients who developed both local and systemic bleeding showed a greater drop in packed cell volume, red blood cell (RBC) count and haemoglobin concentration than those with who did not bleed. No morphological changes in RBCs were seen in blood films. Total white blood cell (WBC) counts were significantly higher in the clinically "more severe" group than in the "less severe" group on admission. Neutrophilic leucocytosis with left shift was present on admission, concurrently with a decrease in eosinophil and lymphocyte counts. These changes tend to become more marked 6h after antivenom therapy, and are greatest in "more severe" envenoming. Thrombocytopenia on admission is positively associated with the development of systemic bleeding and the severity of envenoming. Thrombocytopenia may also be a useful prognostic indicator for the development of local complications, such as necrosis. The intensity of neutrophilia and eosinopenia might be used to follow the progression of necrosis in victims of snake bite.

The efficacies of specific Bothrops atrox-Lachesis and standard Bothrops-Lachesis antivenoms were compared in the north eastern Amazon region of Brazil. The main aim was to investigate whether a specific antivenom raised against the venom of B. atrox, the most important Amazon snake species from a medical point of view, was necessary for the treatment of patients in this region. Seventy-four patients with local and systemic effects of envenoming by Bothrops or Lachesis snakes were randomly allocated to receive either specific (n = 38) or standard (n = 36) antivenoms. In 46 cases (24 in the standard antivenom group, 22 in the other) the snake was identified either by enzyme immunoassay or by examination of the dead snake, as B. atrox in 45, L. muta in one. Patients were similar in all clinical and epidemiological respects before treatment. Results indicated that both antivenoms were equally effective in reversing all signs of envenoming detected both clinically and in the laboratory. Venom-induced haemostatic abnormalities were resolved within 24 h after the start of antivenom therapy in most patients. The extent of local complications, such as local skin necrosis and secondary infection, was similar in both groups. There were no deaths. The incidence of early anaphylactic reactions was 18% and 19%, respectively for specific and standard antivenoms; none was life-threatening. Measurement of serum venom concentrations by enzyme immunoassay (EIA) confirmed that both antivenoms cleared venom antigenaemia effectively. EIA also revealed that one patient had been bitten by Lachesis muta, although the clinical features in this case were not distinctive.