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

Accepted Manuscript Title: Rattlesnakes bites in the Brazilian Amazon: clinical epidemiology, spatial distribution and ecological determinants Authors: Hildegard Loren Rebouc¸as Santos, Jos´e Diego de Brito Sousa, Jo˜ao Arthur Alcˆantara, Jacqueline de Almeida Gonc¸alves Sachett, Thiago Soares Villas Boas, Ivan Saraiva, Paulo Sergio Bernarde, Samara Freire Valente Magalh˜aes, Gisely Cardoso de Melo, Henry Maia Peixoto, Maria Regina Oliveira, Vanderson Sampaio, Wuelton Marcelo Monteiro PII: DOI: Reference:

S0001-706X(18)30881-7 https://doi.org/10.1016/j.actatropica.2018.12.030 ACTROP 4875

To appear in:

Acta Tropica

Received date: Revised date: Accepted date:

2 August 2018 18 December 2018 19 December 2018

Please cite this article as: Rebouc¸as Santos HL, de Brito Sousa JD, Alcˆantara JA, de Almeida Gonc¸alves Sachett J, Villas Boas TS, Saraiva I, Bernarde PS, Freire Valente Magalh˜aes S, de Melo GC, Maia Peixoto H, Oliveira MR, Sampaio V, Monteiro WM, Rattlesnakes bites in the Brazilian Amazon: clinical epidemiology, spatial distribution and ecological determinants, Acta Tropica (2018), https://doi.org/10.1016/j.actatropica.2018.12.030 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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

Hildegard Loren Rebouças Santosa, José Diego de Brito Sousa a,b*, João

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Arthur Alcântaraa,b, Jacqueline de Almeida Gonçalves Sachett a,b,c, Thiago

Soares Villas Boasb, Ivan Saraivac,d, Paulo Sergio Bernardee, Samara Freire

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Valente Magalhãesf, Gisely Cardoso de Meloa,b, Henry Maia Peixotof, Maria Regina Oliveiraf, Vanderson Sampaiog, Wuelton Marcelo Monteiroa,b*

Superior de Ciências da Saúde, Universidade do Estado do

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a Escola

b Instituto

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Amazonas, Manaus, Amazonas, Brazil;

de Pesquisa Clínica Carlos Borborema, Fundação de Medicina

Diretoria de Ensino e Pesquisa, Fundação Alfredo da Matta, Manaus,

Amazonas, Brazil;

Centro Gestor e Operacional do Sistema de Proteção da Amazônia,

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d

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c

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Tropical Dr. Heitor Vieira Dourado, Manaus, Amazonas, Brazil;

Ministério da Defesa, Manaus, Brazil; e Câmpus

de Cruzeiro do Sul, Universidade Federal do Acre, Cruzeiro do Sul,

Brazil; g

de Medicina Tropical, Universidade de Brasília, Brasília, Brazil.

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f Núcleo

Núcleo de Sistemas de Informação, Fundação de Vigilância em Saúde do

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Amazonas, Manaus, Brazil.

*Corresponding author: Dr. Wuelton Marcelo Monteiro. Fundação de Medicina Tropical Dr. Heitor Vieira Dourado/Universidade do Estado do Amazonas. Avenida Pedro Teixeira 25, Dom Pedro, 69040-000, Manaus, AM, 17 Brazil. Phone: 55 92 2127-3430, e-mail: [email protected]

Highlights - We describe cases of envenoming by Crotalus bites in the Brazilian Amazon; - A total of 70,816 snakebites were recorded in the Amazon Region; - Rattlesnake bites incidence was positively associated to tree canopy loss and altitude; - The distribution was irregular between the municipalities in the Amazon State.

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Abstract

Crotalus bites are considered a public health problem especially in Latin

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America. This study was performed to describe the epidemiology, spatial

distribution and environmental determinants of Crotalus durissus bites in the

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Brazilian Amazon. Crotalus durissus envenomings official database included

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cases reported from 2010 to 2015. A total of 70,816 snakebites were recorded

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in the Amazon Region, 3,058 (4.3%) cases being classified as crotalid, with a

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mean incidence rate of 11.1/100,000 inhabitants/year. The highest mean incidence rates were reported in Roraima, Tocantins and Maranhão. Area

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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

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manifestations at admission, delayed medical assistance, lack of antivenom

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administration and ages ≥61 and 0-15 years were predictors of death in C. durissus snakebites. Spatial distribution of rattlesnake bites across the

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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.

Introduction

Crotalus spp, commonly known as rattlesnakes, are among the leading causative agents of snakebites especially in North America. In South America, Crotalus durissus is the most clinically relevant species. Its distribution is

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discontinuous, with many isolated populations in northern South America, including Colombia, Venezuela, Guyana, Suriname, French Guiana,

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southeastern Peru, Bolivia, Paraguay, Uruguay, northern Argentina and

eastern and northern Brazil (Campbell and Lamar, 2004). In the Brazilian

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Amazon, rattlesnakes are present in the states of Rondonia, Amazonas,

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Roraima, Amapá and Pará, and is probably absent in the state of Acre

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(Bernarde, 2014; Vanzolini and Callefo, 2002; Hoge and Romano, 1972), in

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areas of savanna spots, but probably not in the interspersed areas with moist

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broad-leaf and flooded forests (Campbell and Lamar, 2004).

In Brazil, C. durissus bites accounted for 9.2% of cases in 2015. In the

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Brazilian Amazon, there were 341 recorded cases, representing 23.9% of notifications from the country (Brazil, 2018). Epidemiological surveillance

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studies point that C. durissus cause 18.2% in Tocantins (Paula Neto et al., 2005), 13.4% in Roraima (Nascimento, 2000), 0.7% in Amapá (Lima et al.,

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2009), and 0.5% of the snakebites in the Amazonas state (Feitosa et al., 2015a). Bites were also previously recorded in the Marajó Island, state of Pará (Pardal et al., 2007; Pardal et al., 2008) and in Roraima (Mendonça-daSilva et al., 2017).

The clinical manifestations seen in Crotalus durissus are results of neurotoxic, myotoxic and coagulant activities exerted by the venom (Azevedo-Marques et al., 2009). The crotoxin, a major neurotoxin of Crotalus venom, exerts its presynaptic activity by inhibiting acetylcholine release on motor nerve endings, leading to motor and respiratory paralysis. The myotoxic activity is a

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result of the venom-induced skeletal muscle breakdown, often associated with rhabdomyolysis. The coagulant action is attributed to the presence of

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thrombin-like components in the venom, which can lead to

hypofibrinogenemia and blood incoagulability, along with platelet-aggregating

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agents such as convulxin (Azevedo-Marques et al., 2009). The venom of

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Crotalus durissus ruruima, found in the northern state of Roraima and

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southern Venezuela, has shown phospholipase, hemorrhagic and

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edematogenic activities, with a notable intrapopulation variation (Dos-Santos et al., 2005). Clinical manifestations at the bite site generally are little evident,

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with fang marks, paraesthesia and discrete edema and erythema. Systemic manifestations include drowsiness, ptosis, ophthalmoplegia, sagging face muscles, blurred vision, diplopia, myalgia, arthralgia and myoglobinuria. The

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major complications following Crotalus snakebites are acute renal injury and

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respiratory failure, as shown by routine clinical-laboratorial markers (AzevedoMarques et al., 2009). In the Brazilian Amazon, few clinical descriptions of

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Crotalus envenomation have been reported in the state of Pará, evolving to acute renal failure (Pardal et al., 2003). Clotting time can be abnormal in some cases (Azevedo-Marques et al., 2009). Treatment of C. durissus envenomings relies on the administration of a nationally-produced antivenom (Wen et al., 2015).

Interestingly, the burden of snakebites surpasses the clinical and epidemiological limits. In addition to morbidity and mortality, snake envenomation greatly impacts economic determinants in areas of developing countries, increasing costs on hospitalization, treatment and the resulting

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disability of envenomation (Kasturiratne, 2017).

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Little data are available on Crotalus durissus snakebites in the Brazilian Amazon regarding environmental determinants and predictors of

unfavavourable outcomes, with sparce case reports on the literature. Such

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results may aid focused policy-making in order to mitigate the burden, clinical

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complications and death in C. durissus snakebite in the Brazilian Amazon.

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Besides, these data can be exploited for further ecological modeling in the attempt to

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manage Crotalus rattlesnake populations. Henceforth, the aim of this study was

to describe the epidemiology, spatial distribution and environmental

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Methods

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determinants of Crotalus durissus snakebites in the Brazilian Amazon.

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Ethical clearance

This study was approved by the Ethics Review Board (ERB) of the Núcleo de Medicina Tropical of the University of Brasília (approval number 1.652.440/2016). All data analyzed were anonymous. Since data were

obtained exclusively from surveillance databases, a waiver of informed consent was given.

Study design

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The study area comprised the states of Acre, Amapá, Amazonas, Mato

Grosso, Pará, Rondônia, Roraima, Tocantins and Maranhão, whose ecotypes

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are classified in the Amazon biome. This area occupies 5,016,136.3 km 2, corresponding to about 59% of the Brazilian territory, with a population of

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more than 24 million people (IBGE, 2010). Much of the southeast border of

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the Amazon is seasonal forest, marked by a distinct wet and dry season.

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Open ombrophilous forest and semideciduous forest are, in the humid tropical

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hinterland, transitional biomes to savanna. The first represents a transition to the equatorial forest in the Amazon River basin and comprises a huge buffer

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area. The temperature and rainfall are also higher than in the semideciduous forest, although both have a similar level of water seasonality (Arruda et al., 2017) In Brazil, the largest savanna complex is the Cerrado, with further

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islands of savanna of varying size occur throughout the Amazon biome,

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known as Amazonian savannas (Carvalho and Mustin, 2017), despite the

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higher coverage in area by tropical forest.

C. durissus envenomings in humans are conditions of mandatory reporting to the Brazilian Ministry of Health. All variables retrieved from national database were checked for duplicates and completeness by two independent researchers before analysis. The variables analyzed were sex, age (in years),

anatomical region of the bite, area of occurrence (rural or urban), work-related injury (yes or no), time elapsed between the bite and medical assistance (in hours), clinical characteristics, outcome (discharge or death) and antivenom use. Severity classification was made according the Brazilian Ministry of Health guidelines (Table 1). In order to identify factors associated with

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snakebite mortality, a nested case control study was used wherein patients

evolving to severity or death were classified as cases and those discharged

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alive were included as controls.

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Aggregated data by municipality was used to analyze the spatial distribution

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of C. durissus bites cases and its relationship with geographic and

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environmental factors. To identify ecological determinants related to

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snakebites incidence, an ecological study design was carried out including the entire 775 second administrative level subdivisions (municipalities) as units of

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analysis. The cartography also used municipalities as unit of analysis, performed with QGIS (Version 2.18.17 LTR). The dependent variable for mapping was the snakebite incidence, presented as the mean absolute

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number of cases per year, reported from 2010 to 2015, using municipality

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population as denominator (IBGE, 2018), standardizing per 100,000 inhabitants. The rainfall climatology was used to construct seasonality maps

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(Rao and Hada, 1990). Eight geo-environmental factors were included in the analysis as independent variables: (1) Tree canopy loss increase; (2) Area with vegetation cover; (3) Area covered by water bodies; (4) Altitude; (5) Precipitation; (6) Air relative humidity; (7) Soil moisture; and (8) Air temperature.

Definitions

The variables in this study were defined as follows:

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Tree canopy loss: Average annual deforested area in the municipalities between 2007 and 2014, which was measured by the average annual

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percentage of the municipal area that lost forest vegetation; estimated based on the computer assisted analysis of a series of images from Lansat, Cbers,

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UK-2-DMC or Resourcenet. The analysis is performed by

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TerraLib/TerrAmazon project. The detection of deforested area, vegetation

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cover and cloud area are used to estimate the total increment of deforested

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area as described in PRODES methodology, considering the automatically detected area plus the estimated area under cloud cover, according the

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Coordenadoria Geral de Observação da Terra Programa Amazônia (PRODES) (Instituto Nacional de Pesquisas Espaciais, 2013);

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Area with vegetation cover: Percent (%) of municipal area covered by

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vegetation in 2010, automatically detected by the image processing as described in PRODES methodology (Instituto Nacional de Pesquisas

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Espaciais, 2013);

Area covered by water bodies: Percent (%) of municipal area covered by water bodies in 2010, automatically detected by the image processing as

described in PRODES methodology (Instituto Nacional de Pesquisas Espaciais, 2013);

Altitude: Measured as the lowest point within a county in meters above mean sea level using the global digital elevation model geo-processed by Agência

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Nacional de Aviação Civil (Agência Nacional de Aviação Civil, 2018);

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Precipitation: Defined as the deposition of water to surface of Earth, in the form of rain, snow, ice or hail. Is measured in millimeter (mm) and one

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millimeter of rain corresponds to 1 liter per square meter of water on the

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surface. This data were composed from Unified Precipitation Project that are

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underway at NOAA Climate Prediction Center (CPC), every day with spatial

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between 2010 and 2015;

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resolution of 0.5° latitude x 0.5° longitude at surface level (Chen et al., 2008)

Air relative humidity: Defined as the ratio, expressed in percent, of the amount of water vapor in a given volume of air to the amount that this volume

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could contain if the air were saturated (Kalnay et al., 1996); This data were

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composed from National Centers for Environmental National Centers for Environmental Prediction (NCEP) reanalysis, every 6 hours (0 to 18) with

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spatial resolution of 2.5° latitude x 2.5° longitude at surface level (Kalnay et al., 1996) between 2010 and 2015;

Soil moisture: Defined as the water that is maintained in the spaces between soil particles (cm3 water/cm3 soil), in other words the water is available in the

upper layer of soil. This data were composed from National Centers for Environmental National Centers for Environmental Prediction (NCEP) reanalysis, every 6 hours (0 to 18) with spatial resolution of 2.5° latitude x 2.5° longitude between 0 - 10 cm in soil (Kalnay et al., 1996) between 2010 and

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2015;

Temperature: Defined as a quantity of heat that exists in the air and

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measured in degree Celsius (°C). This data were compose from National Centers for Environmental National Centers for Environmental Prediction

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(NCEP) reanalysis, every 6 hours (0 to 18) with spatial resolution of 2.5°

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latitude x 2.5° longitude at 2 meters of the surface (Kalnay et al., 1996)

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between 2010 and 2015.

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Data analysis

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Crude Odds Ratio (OR) with its respective 95% confidence interval (95% CI) was determined considering death as the dependent variable. Differences

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were considered statistically significant for p<0.05. Individual clinical and demographic features were considered as independent variables for this

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analysis.

In the analysis of the ecological determinants of snakebites incidence, the

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eight geo-environmental factors were included in the analysis as independent continuous variables, after colinearity test. A Poisson model was also used to estimate the regression coefficient between snakebites incidence and the geo-environmental factors. Multivariable models were built in a a backward elimination step was performed, resulting in a final model in which only

variables with p<0.05 were kept. The goodness-of-fit of the final model was tested using Hosmer-Lemeshow, p>0.05. In addition, an adjusted model was constructed by including three variables as potential confounders into the model, with equal weights: (1) Human Population Density by municipality, assuming that snakebites are density-dependent, i.e., the contact rate

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between human and Crotalus individuals depends upon the local population

density (Heesterbeek and Metz, 1993); and (2) Access to Health System and

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(3) Health System Effectiveness, subcomponents of the Mean Health System Performance Index (MHSPI) (Reis et al., 2012). Statistical analyses were

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performed using the STATA statistical package version 13 (Stata Corp. 2013).

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Results

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Descriptive epidemiological analysis

A total of 70,816 snakebites were recorded in the Amazon Region in the study period. Of them, 3,058 (4.3%) cases were classified as crotalid snakebites,

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accounting for a mean incidence rate of 11.1 cases/100,000 inhabitants/year.

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Most of the snakebites occurred in males (2,435 cases; 79.6%). Regarding the area of occurrence, 67.9% were reported in rural areas. The most affected

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age group was 16 to 45 years old (1,520 cases; 52.1%). Admixed population was the most reported regarding ethnicity (2.019 cases; 68.5%). The most affected individuals were those with less than 4 years of school education (1,226 cases; 56.2%). A proportion of 43.6% of the snakebites were related to work activities. Most of the snakebites occurred in the lower limbs (82.5%).

Regarding time elapsed from the bite until medical assistance, 82.9% of the cases received treatment within the first six hours from snakebite, 12.5% within 6-24 hours and 4.7% with more than 24 hours. Cases were mostly classified as mild (43.8%) or moderate (43.1%). Lethality was seen in 1.8%

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(Table 2).

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Factors related to lethality from Crotalus bites

Age ≥61 years and time from bite to medical assistance >6 hours, cases classified as severe at admission and lack of antivenom administration were

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associated with the higher odds of death. Age 16-45 years was related to

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protection from death compared to 0-15 years (Table 3).

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Environmental factors related to Crotalus bites incidence

Eight out of nine states reported C. durissus cases during the study period, in 483 (62.3%) of the Amazonian municipalities. The highest incidence rates

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were seen in the states of Roraima (34.61 per 100,000 inhabitants/year), Tocantins (25.67 per 100,000 inhabitants/year) and Maranhão (19.9 per

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100,000 inhabitants/year). No case was reported in the state of Acre and lower incidences rates were reported in the states of Mato Grosso (12.2 per

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100,000 inhabitants/year), Pará (3.61 per 100,000 inhabitants/year), Amapá (3.26 per 100,000 inhabitants/year), Rondônia (1.2 per 100,000 inhabitants/year) and Amazonas (0.1 per 100,000 inhabitants/year (Figure 1). Some municipalities had incidence rates higher than 50 cases per 100,000 inhabitants/year, notably Tupirama (Tocantins; 65.5 per 100,000

inhabitants/year), Vale de São Domingos (Mato grosso; 60.3 per 100,000 inhabitants/year) and Uiramutã (Roraima; 50.9 per 100,000 inhabitants/year).

No clear association was seen between rainiest trimester and C. durissus snakebites. Climate zone that comprises most of the state of Pará and

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northern Maranhão, with the rainiest period from February to April, presented a higher incidence in this season. Climate zone corresponding to southern

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Amazonas, Pará and Maranhão states and northern Tocantins, with the

rainiest period from January to March, also presented a higher incidence in

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this season. Regarding climate zone 4 (states of Mato Grosso and Rondônia

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and southern Tocantins), with the rainiest period from December to February,

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seasonality of snakebites was not evident (Figure 2).

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The mean value of the variables evaluated within the study period, showed

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that air relative humidity presented colinearity with precipitation, and only the latter was kept in the model. In addition, air temperature was not significantly related to bites incidence in the univariate analysis and was not included in

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the final model. After adjustment by human population density, access to health system and health system effectiveness, area with vegetation cover,

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area covered by water bodies, precipitation and soil humidity were negatively related to rattlesnake contact rate. Rattlesnake bites incidence was positively

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associated to tree canopy loss and altitude (Table 4).

Discussion

Few previous attempts have been made to quantify the burden of rattlesnake

envenomings in the Brazilian Amazon. A total of 3,058 cases of Crotalus durissus snakebites were reported in the study period, namely impacting male individuals aged between 16 to 45 years. This study confirms previous surveillance based reports in the region that C. durissus bites affect mostly adult males, living in rural areas and related to work activities (Feitosa et al.

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2015a; Lima et al., 2009). This profile reaffirms the strong relationship

between snakebites and rural economical activities, negatively affecting family

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economies in the area (Feitosa et al., 2015b). Such finding, similarly observed in accidents by other venomous agents, may be a result of greater exposure

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to snakes during leisure and work-related activities such as open-field hunting

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(Pardal et al, 2007).

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Clinical descriptions of 13 cases reported from the Brazilian Amazon show only mild local manifestations, neurological manifestations, namely palpebral

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ptosis, diplopia, ophtalmoplegia and dizziness, as the predominant symptoms for C. durissus bite cases (Pardal et al., 2007; Mendonça-da-Silva et al., 2017). Renal failure was recorded in one patient (Pardal et al., 2007). After

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the antivenom therapy and symptomatic measures, all patients evolved with

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good prognosis. Lethality arising from C. durissus bites was estimated in 1.8%, higher than the overall mortality from snakebites in the Amazon, where

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Bothrops envenomings predominate (Feitosa et al., 2015b). The best predictor of death was severe manifestations at admission, such as myasthenic face and blurred vision, intense myalgia, darkened urine and oliguria/anuria (Brazilian Misnitry of Health, 2017). Treatment of choice for crotalid envenomings relies on the administration of specific antivenom and

supportive treatment in the presence of systemic complications, including renal replacement therapy in acute renal failure, artificial ventilation in respiratory failure, and corticosteroids, antihistamines, and epinephrine in case of anaphylactic reactions following antivenom administration (Brazilian Misnitry of Health, 2017). Similarly, to other envenomations in the Brazilian

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Amazon, geographical peculiarities of the region along with distance to

specialized health care facilities represent a major hindrance in access to

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prompt and specialized medical treatment, especially in isolated areas of the

Brazilian Amazon (Feitosa et al., 2015a; Wen et al., 2015). Thus, association

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of death with delayed medical assistance and lack of antivenom

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administration is plausible.

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Age ≥61 and <15 years groups presented higher odds of death. In Crotalus

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durissus snakebites reported in São Paulo, Brazil, patients ≥50 years old had

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a higher mortality when compared to younger patients (Ribeiro et al., 1998). Taking into account that most snakebite complications, especially by C. durissus, are due to acute renal failure (Pinho et al., 2005; Pinho et al., 2008;

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Amaral et al., 1986), the greater severity associated with the elderly may be

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related to higher prevalences of chronic comorbidities (i.e. hypertension and diabetes) that can predispose to necrosis and acute kidney injury after a bite

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(Albuquerque et al., 2013; Albuquerque et al., 2014). Age less than 15 years was also an independent risk factor for severity, as also observed in in other studies (Sankar et al., 2013; Feitosa et al., 2015a), probably as a result of smaller body volumes to higher antigenemias (Chippaux, 1998).

Geographical distribution of rattlesnake bites across the Brazilian Amazon show higher incidence in Roraima and in the transitional landscapes in the south and in the east side of the region. In these areas, rattlesnake bites incidence was notably higher in municipalities with a higher tree canopy loss and lower vegetation cover. The distribution of rattlesnake bites in the

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Amazon precisely overlaps with the Crotalus durissus territory occupation in the Amazon, in relictual savanna spots in the states of Rondônia (França et

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al., 2006; Silva, 1993), Amazonas (Humaitá and Parintins) (Hoge and

Romano, 1972), Roraima (França et al., 2006; Wüster et al., 2005), Amapá

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(França et al., 2006), and Pará (Santarém, Monte Alegre, Serra do Cachimbo,

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Oriximiná, Salvaterra, and municipalities of the Marajó Island) (Rodrigues et

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al., 2016; Yuri and Santos, 1996), Mato Grosso (Silva, 1993; Wüster et al.,

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2005; Carvalho and Nogueira, 1998), Maranhão (Lira-da-Silva et al., 2009;

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Ferreira et al., 2005), Tocantins (Amaral, 1935; Vitt et al., 2005).

In this study, however, association of rattlesnake bites incidence and seasonality was not evident, as well as area with the percentage of water

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bodies coverage, as previously flagged in studies regarding pit vipers

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(Bothrops genus) snakebites, whose incidence has a clear seasonal pattern related to the flooding in lowland rainforest, forcing the snakes to upland

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areas, increasing the likelihood of contact between humans and snakes (Feitosa et al., 2015b). Rattlesnakes, in their turn, are adapted to savanna ecotopes, which despite presenting a pronounced seasonality, is significantly drier than the interior Amazon forest and has an increased tendency to the establishment of scleromorphic species, being less influenced by flooding

(Carvalho and Mustin, 2017; Arruda et al., 2017; Arruda et al., 2018). In Central Brazil, C. durissus exhibits a peak of activity between April and May (Salomão and Almeida-Santos, 2002). Mating occurs from April to June (Salomão and Almeida-Santos, 2002) and juvenile recruitment, from December to August (Almeida-Santos et al., 2004). In the Amazon, to the best

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of our knowledge, there are no published information about studies conducted

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in the field, which could affect contact with humans.

Although moist forest is the most protected Brazilian ecoregion type in the

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Amazon, the same level of protection does not extend to its savannas and

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ecotonal areas, which represent the original areas where rattlesnakes occur

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(Mustin et al., 2017). Amazonian savannas are highly threatened, principally

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as a result of land-grabbing and the advance of cultivation of grains and pulses (mainly soybeans, maize, upland rice and beans), pastures,

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plantations of exotic species (eucalyptus and acacia), and uncontrolled fires (Carvalho and Mustin, 2017; Mustin et al., 2017). Building of rural access roads and their maintenance is much less problematic when there is a distinct

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dry season. The same holds for infrastructural facilities at the settlement

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centers, whether such centers are oriented on agricultural produce, or engaged in mining, logging or nontimber forest product gathering (Sombroek,

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2001; Carrero and Fearnside, 2011). After deforestation, extensive soybean cropland and pastures are associated to reduction in precipitation in this area, expanding open fields (Sampaio et al., 2007; Costa and Pires, 2010). Crotalus durissus is likely to be found in anthropized areas especially due to deforestation (Sant’Anna and Abe, 2007; Bastos et al., 2005), where

deforested areas mimic the vegetation coverage usually seen in cerrado (Tozetti and Martins, 2013; Duarte and Menezes, 2013).

In the Amazon basin, annual rainfall decreases, and the length of the dry season increases, from west to east and north to south of the region. An

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average rainfall is made around 2,300 mm. year-1, reaching 3,500 mm.year-1 in the northwest of the region (Figueroa and Nobre, 1990). In this context,

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relative air humidity is directly modulated by rainfall and presents higher

values during the rainy season of each region, but as the largest varieties

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occur in the northern Amazon, with minimum values around of the 30%, in

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savanna areas (Figueroa and Nobre, 1990). These characteristics explain the

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negative association of rattlesnake bites incidence with precipitation and soil

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humidity. Regarding soil moisture, it is known that rainfall, the most natural source of soil water in the region normally is reduced during in savanna drier

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lands. Differencial patterns of soil type, incident total solar radiation, evaporation and evapotranspiration are other factors that deplete soil

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moisture in the area (Rocha et al., 2009; Maeda et al., 2017).

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Rattlesnake bites predominate in highest landscapes, especially in highaltitude areas of the Roraima state, which traverse the northern border with

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the Guianas and Venezuela, followed by municipalities located in the Brazil's Central Highlands include a vast uneven plateau that has an average elevation of 1,000 meters. The rest of the Amazonian territory is made up primarily of sedimentary basins, the largest of which is drained by the Amazon and its tributaries, presenting few or even an absence of records. In general, it

is expected that elevational reptile richness and snakebites are most strongly correlated with temperature, mediated by precipitation, and decreases in high landscapes (McCain, 2010; Chettri et al., 2010). However, with a less vegetation richness in savannas along the elevational degrees, in relation to other ecotopes, this effect may influence on activity and abundance of

IP T

rattlesnakes. Furthermore, rattlesnakes are generalists regarding the

microhabitat variables and present low thermal selectivity, being able to

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colonize the amplitude of ecotopes, from lower ecotonal areas to savannas of a range of elevations (Tozetti and Martins, 2013; Rodrigues and Prudente,

U

2011). Moreover, climatic variables such as air temperature and rainfall have

N

little influence on the activity pattern of rattlesnakes (Tozetti and Martins,

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A

2013).

Lastly, as national surveillance databases were used to gather all data from

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C. durissus snakebites, this study had limitations. Usually, there is no professional health care agent trained on snake identification at notifying unit. Thus, misinformation on causative species due to wide range of similar

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different species in the Amazon may over- or underestimate the real burden of

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such snakebites. Local knowledge on specific snake identification is overlapping among species and states, hampering precise description of

A

snakes and notification.

Conclusion

In the Amazon, severe manifestations at admission, late medical assistance,

lack of antivenom administration and ages ≥61 and <15 years are contributing factors to a higher proportion of death in C. durissus snakebites, especially in areas of savannas, differing from other native species of snakes. The burden of such snakebite is evident, and these results may aid focused policy-making and public health campaings in order to mitigate the burden, clinical

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complications and death in C. durissus snakebite. Ecological determinants can also be used as a proxy for further ecological modeling to manage

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Crotalus rattlesnake populations.

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Figures

Figure 1. Incidence of Crotalus snakebites across states of the Brazilian

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Amazon, 2010 to 2015.

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Figure 2. Annual distribution of cases of Crotalus snakebites per climate zone

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in the Brazilian Amazon.

Table 1. Severity classification and antivenom regimen recommended by the Brazilian Ministry of Health. Case severity Marker Moderate

Severe

Myasthenic face and blurred vision

Absent or late

Absent or late

Evident

Myalgia

Absent or late

Mild

Intense

Darkened urine

Absent

Absent or little evident

Present

Oliguria/anuria

Absent

Absent

Clotting time

Normal or prolonged

Normal or prolonged

Vials of CAV*/BCAV**

5

10

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U

N

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Mild

Absent or present Normal or prolonged 20

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*CAV, crotalid antivenom; **BCAV, bothropic-crotalid antivenom.

Table 2. Epidemiological characteristics of 3,058 Crotalus snakebite cases reported in the Brazilian Amazon, 2010 to 2015. Variable (n; %)

Number

%

Female

623

20.4

Male

2,435

79.6

0-15

544

18.6

16-45

1,520

52.1

46-60

558

19.1

>61 years

295

10.1

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Age range (in years; 1,109; 93.9%)

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Sex (3,058; 100.0%)

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Ethnicity (2,948; 96.4%)

360

12.2

325

11

28

0.95

2019

68.5

216

7.3

2,012

67.7

938

31.6

15

0.5

Yes

1,143

43.6

No

1,481

56.4

Illiterate

338

15.5

≤4

888

40.7

5-8

495

22.7

>8

460

21.0

N

White

A

Black Yellow

M

Mixed

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Indigenous

Area of occurrence (2,965; 97.0%) Rural Urban

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Periurban

CC

Work-related (2,624; 85.8%)

A

Education level in years (2,181; 71.3%)

Site of bite (3,034; 99.2%) Upper limb

441

14.4

Lower limb

2,505

82.5

Other

48

1.6

≤ 6 hours

2,395

82.9

6-24 hours

361

12.5

>24 hours

137

4.7

SC R

Case severity (2,873; 93.9%)

IP T

Time to medical assistance (2,890; 94.5%)

1,259

43.8

Moderate

1,237

43.1

Severe

377

13.1

2,561

98.2

46

1.8

U

Mild

A

Discharge

N

Case evolution (2,607; 85.2%)

A

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Death

Table 3. Epidemiological factors associated with case lethality in Crotalus snakebites in the Brazilian Amazon. p

1.23 (0.43-3.47)

0.69

1.39 (0.72-2.72)

0.32

1 0.47 (0.21-1.05) 0.93 (0.39-2.21) 2.09 (0.89-4.89)

... 0.06 0.87 0.08

A

M

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EP

CC A

SC R

IP T

OR (CI95%)

... 0.71 0.17

1 1.33 (0.44-4.03) 0.36 (0.08-1.63) 0.50 (0.09-2.79)

... 0.62 0.18 0.43

0.75 (0.39-1.42)

0.38

1 0.77 (0.33-1.84)

... 0.56

1 5.07 (2.58-9.96) 6.86 (2.85-16.54)

... <0.001 <0.001

U

1 0.81 (0.27-2.46) 0.53 (0.22-1.31)

N

Variable Area of occurrence Rural Sex Female Age group (in years) 0-15 16-45 46-60 ≥61 Ethnicity White Black Mixed Education level (years of study) Illiterate ≤4 5-8 >8 Work-related snakebite Yes Anatomical region bitten Lower limbs Upper limbs Time from bite until medical assistance (hours) ≤6 >6-24 >24 Severity grading at admission Mild Moderate Severe Antivenom administration No Antivenom dosage As recommended Underdosage

1 ... 1.65 (0.54-5.07) 0.37 23.81 (9.19-61.64) <0.001 6.56 (2.96-14.55)

<0.001

1 1.13 (0.53-2.39)

0.73

Table 4. Association of geo-environmental variables with Crotalus snakebite incidence rates in the Brazilian Amazon in the multivariate analysis. Adjusted Coef. [Final model] (CI 95%) 0.0041 (0.0054; 0.0029) -0.0077 (-0.0098; -0.0056) -0.0172 (-0.0274; -0.0071) 0.0013 (0.0015; 0.0010) -0.00015 (-0.0001; -0.0002) -0.1872 (-0.2182; -0.1562)

p <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001

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Variable Tree canopy loss (%) Area with vegetation cover (%) Area covered by water bodies (%) Altitude (meters above sea) Precipitation (millimeters) Soil humidity (cm3 water/cm3 soil)

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A

N

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Legend: Adjusted by human population density, access to health system and health system effectiveness.