Scorpion envenomation in the state of São Paulo, Brazil: Spatiotemporal analysis of a growing public health concern.

Scorpion envenomation is a significant public health concern in São Paulo, Brazil, and its incidence and mortality have increased in recent decades. The present study analyzed documented scorpion envenomation notifications from 2008 to 2018 throughout the 645 municipalities of São Paulo. Annual incidence and mortality rates were calculated and stratified according to sex and age. The local empirical Bayesian method and Getis-Ord Gi* statistic were used to represent standardized incidence rates in the municipalities and to identify high- and low-risk agglomerates. The incidence rate of scorpion envenomation quintupled between 2008 and 2018. Overall, the risk was higher for man, and increased with age. Deaths due to envenomation, however, were concentrated almost entirely in children 0-9 years of age. Incidence maps showed that the risk of envenomation increased in almost all regions and municipalities of São Paulo throughout the study period. The highest incidence rates were found in the western, northwestern and northern regions of the state, in contrast to the São Paulo metropolitan area and southern and coastal regions. Hot spots were identified in the Presidente Prudente, Barretos, São José do Rio Preto, and Araçatuba regional health districts, which over time formed a single high-risk cluster. In spatial terms, however, deaths were randomly distributed. In this study, we identified areas and populations at risk of scorpion envenomation and associated-fatalities, which can be used to support decision-making by health services to reduce human contact with these arachnids and avoid fatalities, especially in children.

Introduction

There are many venomous animals with toxins that are potentially harmful to humans among the world’s diverse fauna. Envenomations that can cause severe injuries or sequelae, particularly those with socioeconomic and medical repercussions, are considered important from a public health perspective, as they can result in temporary or permanent injuries and even fatalities [1]. Scorpions can inflict such envenomations, resulting in a significant and emerging public health concern, especially in the Middle East, India, Mexico, and Brazil [2-4].

There are approximately 2,621 species of scorpion worldwide, belonging to 23 distinct families [5]. Of these, only 30 are considered harmful to humans, 29 of which belong to the Buthidae family. In South America, and particularly in Brazil, Tityus is the most medically relevant scorpion genus due to the clinical manifestations caused by envenomations in humans and the high incidence in recent years [2, 3, 6]. There are four epidemiologically significant species in Brazil: Tityus serrulatus, T. bahiensis, T. obscurus, and T. stigmurus [7, 8]. The high incidence and severity of, as well as the difficulty controlling scorpion stings, in some tropical countries, have made envenomations a public health concern. In these countries there are more than 1,200,000 envenomations annually, resulting in over 3,000 deaths [2].

From a clinical point of view, scorpion envenomations can be classified as mild, moderate, or severe [7, 9–12]. In mild cases, the toxins in the scorpion venom usually cause local effects, while systemic symptoms of autonomous nervous system imbalance, including nausea and vomiting, sweating, tachycardia, tachypnea, and mild hypertension occur in moderate cases. Severe envenomations are generally associated with cardiovascular, pulmonary, metabolic, and neurological complications, and can result in death, especially in children under 10 years of age [7, 9, 12–14]. According to the Brazilian Ministry of Health Guidelines, antivenom treatment is recommended in which the patient presents with signs and symptoms of systemic envenomation, which are classified as moderate or severe cases depending on the severity of the clinical manifestations [11, 14, 15].

Although the vast majority of scorpion envenomations in Brazil are considered mild with benign outcome [16], numerous severe cases occur, with some resulting in deaths. According to Reckziegel and Pinto (2014) [17], the highest rates of scorpion envenomations and deaths were observed in the northeast and southeast regions of Brazil, between 2000 and 2012. In the southeast region, the average annual incidence was 19.1 cases per 100,000 inhabitants, with the state of São Paulo (SP) accounting for 13.3% of all cases and 3.4% of the total envenomation-related deaths recorded in the country during this period.

In Brazil, envenomations due to scorpion stings are a significant public health concern because of their increasing incidence, which is related to the close proximity of scorpions to humans, as well the adaptation to their habitat. Monitoring and control of these arachnids are essential to eliminate, or at least minimize, the risk of death due to an envenomation [18]. For this reason, it is extremely important to characterize scorpion envenomations in terms of the people affected by the stings, as well as, spatiotemporal factors.

Few studies have addressed scorpion envenomation in geographic terms [19-21], despite the evident influence of the environment, climate, and human occupation [21-25]. Spatial analysis tools available now offer results that can strengthen decision-making strategies and guide efforts to target higher-risk areas in an effort to fill in this knowledge gap. As such, the present study aimed to describe the occurrence of scorpion envenomations in SP between 2008 and 2018 based on case data, and assesses the temporal and spatial distribution of these envenomations to identify areas at higher or lower risk, with the goal of assisting in the development of strategies with which to monitor and control these epidemiological events.

Methods

Type, period, population, and study area

This descriptive and ecological study utilizes secondary data on scorpion envenomations in SP between 2008 and 2018; the data unit considered during analysis was each municipality in the state. SP is located in southeastern Brazil (Fig 1), and includes 645 municipalities, which are divided into 17 Regional Health Districts (RHDs). With 46,289,333 inhabitants, the population density of SP is 166.23 inhabitants/km2; it has the second-highest Human Development Index (HDI) score of any Brazilian state (0.783) [26].

Fig 1

Location of the state of São Paulo in Brazil and South America, its relief and the regional health departments (RHDs).

The state of SP has three primary climates. According to the Köppen-Ginger classification scheme, the western plateau of the state has a tropical climate (Aw) characterized by wet summers and dry winters. The higher altitude regions located in the Atlantic plateau and basaltic cuestas have a high-altitude tropical climate (Cwa and Cwb), whcih is characterized by hot summers and cold winters. The lowland coastal region has a humid tropical climate (Af), which is characterized by being hot and humid all year round. The annual rainfall varies between 1,600 mm on the south coast and 2,700 mm on the north coast. Finally, the peripheral depression has a subtropical climate (Cfa), which is characterized by the occurrence of well-distributed rainfall throughout the year, with hot summers and cold winters [27]. Although very little of the vegetation native to SP remains, largely due to the agriculture of sugar cane and pastures, the state’s territory has three types of vegetation cover: mangroves are found in the coast; patches of savanna are found in the peripheral depression and on the eastern border of the western plateau; and the predominant vegetative throughout the rest of the state is the Atlantic Forest (Fig 1) [28].

Data source, variables, and data analysis

Data regarding scorpion envenomations were obtained from the Brazilian Information System for Notifiable Diseases (SINAN) and were provided by the São Paulo State Epidemiological Surveillance Center (CVE). Geographic and demographic information on the municipalities was obtained from the Brazilian Institute of Geography and Statistics (IBGE), including shape maps. This information was entered into a database, and is also available in S1 File.

We calculated the incidence and mortality rates of scorpion envenomations in SP throughout the study period, taking age and sex into consideration. These rates were calculated annually and standardized by age and sex using the population of SP in 2013 as the standard. Linear and quadratic regression models were used to analyze the temporal series, and the rates were modelled per calendar year as a function of the year and the year raised to the square, respectively. We used the Shapiro-Wilk (SW) test to assess the normality of the residuals, and the Durbin-Watson (DW) test to assess the existence of temporal autocorrelation, for which DW = 0 was considered to correspond to the existence of positive autocorrelation, DW = 2 to no autocorrelation, and DW = 4 to negative autocorrelation [29]. Incidence rates for scorpion envenomations were calculated annually for the municipalities of SP and standardized by age and sex. We mapped these rates using the local empirical Bayesian method with the queen criteria for neighborhood contiguity between municipalities. The entire population of SP from 2013 was considered the standard, and the results of these analyses are presented as choropleth maps, which also include data regarding municipalities with deaths.

We utilized the Getis-Ord Gi* spatial analysis of the calculated incidence rate for the municipalities of SP to identify clusters with high and low risks of scorpion envenomations for each year of the study. This technique considers a neighborhood matrix between municipalities, and identifies local spatial associations. The results were allocated to each municipality to develop statistical maps. In the Gi* statistics, high values indicate areas of increased occurrences of the event/phenomenon, and low values indicate groupings of decreased occurrences [30]. Finally, we used the false discovery rate (FDR) to avoid the problem of multiple comparisons in local statistics; this method can prevent false positive clusters, and more efficiently filter the real spatial agglomerates of interest [31].

Ethical considerations

The present study was developed using secondary data provided by the CVE (Secretary of Health of the state of São Paulo). The data form which was anonymized without names or addresses, and scorpion accidents were aggregated by municipality and year. The protocol for the present study was submitted for approval by the institutional ethics review board of the University of São Paulo School of Public Health (COEP FSP/USP, CAAE approval record 10457119.6.0000.5421, protocol number 3408558) and no consent was required because we used anonymized secondary data.

Results

Between 2008 and 2018, there were 145,464 scorpion envenomations documented in the 645 municipalities of SP (Table 1). A 425% increase was observed from 2008 (5,788 cases) to 2018 (30,394 cases).

Table 1

Number of cases and deaths resulting from scorpion envenomation by age and sex and respective rates of incidence (100,000 inhabitant-years) and mortality (1,000,000 inhabitant-years) in the state of São Paulo, Brazil from 2008–2018.

Sex	Incidence and mortality rate	Age group
		0-9 years	10-19 years	20-39 years	40-59 years	60+ years	Total
Male	Incidence	19.3	26.2	33.8	42.5	52.9	34.7
	(N)	6605	10006	27024	24995	13433	82063
	Mortality	0.79	0	0	0.02	0.08	0.13
	(N)	27	0	0	1	2	30
Female	Incidence	16.7	24.3	25.2	29.6	32.4	26
	(N)	5481	8916	19907	18413	10684	63401
	Mortality	0.46	0.03	0.01	0.02	0	0.07
	(N)	15	1	1	1	0	18
Total	Incidence	18	25.3	29.5	35.8	41.3	30.3
	(N)	12086	18922	46931	43408	24117	145464
	Mortality	0.63	0.01	0.01	0.02	0.03	0.1
	(N)	42	1	1	2	2	48

The incidence and mortality rates of scorpion envenomations were 33% and 86% higher in men than in women, respectively, throughout the study period. These rates were also higher in men of all age groups, with the exception of mortality in the young adult age groups. Incidence rates increased with age, at 68% higher for people aged 60 years and over than for children aged 0–9 years, while mortality exhibited a distinct trend, and was concentrated in children younger than 9 years of age, with 42 of the 48 documented deaths (88%) occurring in this age group. These results demonstrate that although adults are more likely to be envenomated, children are at a higher risk of death from envenomation.

The incidence rate of scorpion envenomations quintupled in SP between 2008 and 2018, gradually increasing from approximately 14 cases per 100,000 inhabitants in 2008 to 70 in 2018 (Fig 2). Mortality from scorpion envenomation was constant in SP from 2008 through 2014, from which point it increased significantly, with approximately 0.3 deaths per 1 million inhabitants in 2018, a 244.2% increase in the period.

Fig 2

Incidence and mortality rates of scorpion envenomations per year in the state of São Paulo, Brazil from 2008–2018.

Table 2 presents the results of the quadratic regression models for incidence and mortality, which all coefficients (intercept, year, and year squared) were significant or at their limit (year, in the incidence model). Since the models used for incidence and mortality correspond to second-degree functions with a positive quadratic term coefficient, both incidence and mortality rates clearly showed a significant increase between 2008 and 2018.

Table 2

Ordinary least squares quadratic regression models for temporal modeling of incidence and mortality rates for scorpion envenomations in the state of São Paulo, Brazil from 2008 to 2018, and the results of the Durbin-Watson and Shapiro-Wilk tests.

Variables, tests and R2	Incidence rate		Mortality rate
	Coefficients/tests	p values	Coefficients/tests	p values
Intercept	18.082	0.0004	0.103	0.0138
Year	-2.647	0.0554	-0.036	0.022
Year2	0.604	0.0002	0.005	0.002
Durbin-Watson (DW)	1.8098	0.1137	2.7858	0.7381
Shapiro-Wilk (SW)	0.9759	0.9388	0.9837	0.9832
R2	0.9766		0.8918

We opted to use quadratic regression models because the linear models were not sufficient to adjust for temporal autocorrelation. For incidence, the DW value of the model, without quadratic adjustment was 0.72, with R2 = 0.86, whereas with the quadratic adjustment, the DW value was 1.80, R2 = 0.97, showing improvement and adjustment of the model for the series autocorrelation. For mortality, the DW value without quadratic adjustment was 1.20, with R2 = 0.61, while with adjustment the DW value was 2.78, R2 = 0.89, also showing improvement and adjustment of the model for the series autocorrelation. The SW normality test for the residuals of the models for incidence and mortality did not reject the hypothesis of normal distribution in these time series.

The western, northwestern and northern regions of SP, which are part of the western plateau (Fig 1), had the highest numbers of scorpion envenomations during the study period (Figs 3 and 4). The highest incidence rates were found in the São José do Rio Preto, Barretos, Presidente Prudent and Araçatuba RHDs, although Araçatuba was the only municipality which reported two deaths, both in children, in the same year during the study period, 2018. Meanwhile, incidence rates were lowest in the southern, eastern, and coastal regions of SP, as well as in the metropolitan region surrounding the capital city of SP.

Fig 3

Maps of standardized local empirical Bayesian incidence rates (per 10,000 inhabitant-years) and deaths from scorpion envenomations for municipalities in the state of São Paulo, Brazil from 2008–2018.

Fig 4

Standardized incidence rates of scorpion envenomations (per 10,000 inhabitant-years) for the Regional Health Districts (RHDs) located in the western, northern, northwestern, and central portion (A), and in the eastern and southern portion (B) of the state of São Paulo, from 2008 to 2018.

Over time, an increase in scorpion envenomation incidence rates can be seen in almost all of the municipalities (S1 Fig) and RHDs of SP (Fig 4), corresponding to the temporal increase identified throughout the study period. This increase was much more pronounced in the western, northwestern, and northern regions of the state. The central region of the state, particularly the Piracicaba RHD (which had more moderate growth), acts as a division between the large increase in envenomations in the west and a smaller increase in the east. Spatially, the deaths were spread out randomly, but for each calendar year, they primarily remained in the central, northern, and western regions of the state (Fig 3).

The Gi* statistic clusters were identified by applying FDR adjustment, so that the agglomerates would be more representative and accurate. This adjustment made it possible to identify whether an area had a higher or lower potential for scorpion stings. Fig 5 depicts two hotspots in red: one in the Barretos and São José do Rio Preto RHDs, and the other in the Araçatuba and Presidente Prudente RHDs, both in 2008. Over time, these high-risk agglomerations grew to include more municipalities, until a single cluster involving these four health districts was formed in 2018. This unification is in line with the higher numbers of scorpion envenomations in the western, northwestern, and northern regions of SP, as well as the temporal increase in incidence rates. Meanwhile, cold spots, or those with lower risks, occurred in the same areas, which were identified as having lower incidence rates, namely the southern, eastern, and coastal regions of the state, as well as the São Paulo metropolitan region.

Fig 5

Spatial clusters of the Getis-Ord Gi* statistic with false discovery rate (FDR) adjustment for municipalities in the state of São Paulo, Brazil from 2008–2018.

Discussion

Reckziegel & Pinto (2014) [17] have already demonstrated the increase in scorpion envenomation, and the subsequent increase in scorpion-related deaths, in Brazil, in their assessment of incidents between 2000 and 2012. They found growth throughout all Brazilian states similar to we found in SP. Additionally, our findings regarding the age group in which envenomation-related deaths occurred are corroborated by other authors in Brazil [17, 32–34], as well relevant international literature [35, 36]. This trend indicates the need for more adequate health measures to reduce the number of scorpion envenomations occurring in these regions, in an effort to avoid deaths in the most vulnerable group (children aged 0–9 years).

The association between the severity of the envenomation and the age group was attributed to the proportion of venom injected in relation to body surface, and a positive association was found between the severity of the envenomation and the amount of venom in the plasma [37]. Reduced levels of circulating vasoactive mediators, such as epinephrine and angiotensin-converting enzyme, were found in children who had experienced a severe envenomation [38]. Additionally, it is possible that the heart and other organs may absorb more venom in this age group [39]. Meanwhile, the occurrence of severe cases among the elderly is most likely due to comorbidities, which affect the cardiovascular system in this population. Regardless, in any age group, a poor prognosis is clearly associated with delays in determining severity and in specific treatment with scorpion or arachnid antivenom.

One reason for the increase in the incidence rate of scorpion envenomations in SP is the continued improvement of the notification system for these accidents, as well as the increased demand for health care from patients affected by scorpion stings in Brazil [40]. The introduction of an internet version of SINAN in 2007 (SINAN Net), for example, improved the operationalization of notifications and the precision of data collection. With the increase in the number of notifications of the accidents and the related deaths, the health system itself became more sensitive, communicating more effectively with the population about the severity of scorpion stings. The media is also involved in this communication circuit, helping to make the population aware of the need for prevention of scorpion accidents, while increasing their sensitivity to the problem, driven them to seek care within the healthcare system when they experience a scorpion sting [40, 41]. The implementation of the scorpion control program in 2009 has played an important role in this scenario [42], as this program has driven improved communication with society, training human resources and the control and environmental management of scorpion infestation throughout Brazilian municipalities (MS 2009).

Additionally, ecological, climate and socioeconomic factors can be associated with the worsening epidemiological picture of scorpion envenomations in SP. A major factor associated with the growing incidence rate of envenomation in SP that we identified in the present study is the replacement of T. bahiensis by T. serrulatus as the primary scorpion species across nearly the entire state of SP. In a study on the occurrence of medically relevant scorpions in SP, Candido (2008) [43] identified this change, and attributed it primarily to parthenogenesis in T. serrulatus. The increase in stings and subsequent deaths may be related to the fact that this species causes more severe envenomations than T. bahiensis, and also to a continued increase in T. serrulatus infestation [44], which in turn may be related to factors such as urbanization and climate change. T. serrulatus typically colonizes in urban areas (cities and villages), and can be easily unknowingly transported between cities by humans. For example, Brasília was invaded and colonized by T. serrulatus in less than 15–20 years [45, 46].

The growing process of urbanization, precarious living conditions, human behavior, and high ecological plasticity of some clinically relevant scorpion species, such as T. serrulatus and T. stigmurus, may affect the epidemiology of envenomations [47]. Disorderly urban growth can therefore be considered a determining factor in the proliferation of scorpions, where the generation and accumulation of debris plays a fundamental role in the availability of breeding habitats, as these conditions facilitate the spread of cockroaches and other insects that are primary food sources for scorpions [48]. Expanding agricultural frontiers combined with clearing of native vegetation also contributes to the higher incidence of scorpion stings, since the destruction of scorpions’ natural habitats and that of their natural predators (such as monkeys, raccoons, frogs, owls, and lizards) causes an ecological imbalance followed, by a subsequent boom in scorpion populations [17, 49].

The positive selection of harmful opportunistic species is directly associated with human activity. In profoundly modified environments, such as several "artificial" cities in Brazil, the human population begins to grow rapidly, and the three main factors required for high incidences of scorpion envenomations in these regions became present: first, the demographic expansion of the human population; second, the rapid expansion of populations of harmful opportunistic scorpions that can occupy the empty niches left behind when species in equilibrium diminish or go extinct, and in many cases, opportunistic species adapt their behavior and move into human dwellings; and third, the overlap between a large human population and a large population of harmful scorpions greatly increases the likelihood of scorpion stings [50], a situation which is typical in several regions of Brazil, although primarily in the southeast and Midwest regions.

An additional factor that may be related to the increase in scorpions, and therefore scorpion stings, is climate change, which affects the entire planet. It has severely affected the environment, and may influence the distribution of arthropod populations. In a recent study on how climate affects scorpions in Iran, Rafinejad et al. (2020) [25] emphasized that climate change is an important variable in the spatial distribution of these arthropods, because their activities are highly dependent on environmental conditions. For example, higher temperatures may shorten the procreation times while increasing the maturation rate of scorpions.

Needleman et al. (2018) [51] stated that climatic effects are closely linked to land-based venomous species, and that environmental changes could result in greater species migration, geographical redistribution, and longer periods with more stings, which would have repercussions for human health. All three of these hypothetical impacts have been seen in SP. The first was the near-total replacement of T. bahiensis (which had been the predominant species) by T. serrulatus, which is parthenogenetic and successfully adapted to profoundly modified environments [43, 52]. Braga-Pereira & Santos (2021) [53] also showed that parthenogenetic reproduction in T. serrulatus can occur not only in asexual populations of this species, but also in those where sexual reproduction occurs—in other words, parthenogenesis is optional in T. serrulatus. The second and third hypotheses raised by Needleman et al. (2018) [51], regarding geographical redistribution and a continued increase in the number of scorpion stings, also correspond to the results of the present study. Abreu et al. (2019) [54] noted that higher temperatures in southeast Brazil between 1995 and 2004 would have been appropriate for the proliferation of scorpions in this region. The findings of the present study confirm the increased incidence of scorpion stings in almost all municipalities and regions of SP, while also demonstrating that these incidences are not evenly distributed in the municipalities in which they occur. At they are more numerous in the western, northwestern, and northern regions. These regions are part of the western plateau of SP, and have the highest temperatures and lowest rainfall in SP [27], which favors the development of scorpions [25, 55]. Ureta et al. (2020) [56] also studied the impacts of climate change on scorpions, using ecological niche modeling in Mexico, from whichthey identified the dispersion and geographical redistribution of some scorpion species among the country’s regions.

In an analysis of notifications and government outreach services resulting from scorpion sightings by the public in SP, Morais et al. (2021) [44] found higher numbers of scorpions in the western, northwestern, and northern regions of the state. The monitoring system revealed higher numbers of scorpion notifications in the Ribeirao Preto, Araçatuba, Presidente Prudente, Barretos, and São José do Rio Preto RHDs, and lower numbers in the Baixada Santista RHD. In a study of scorpion stings in SP between 2000 and 2011 with future predictions, Azevedo et al. (2019) [49], also noted an increased probability of envenomations due to climate change, and authors showed that this increase is related to changes in temperature amplitude, and is therefore expected to be more pronounced in the western, northwestern, and northern regions of the state; specifically the regions we found to be most affected.

There are, of course, limitations to the present study. The first is that it is based on secondary data on passive notifications of scorpion stings. Two possible biases are relate to this point: the notification system is subject to underreporting, which can generate incidences lower than the actual values, although the system has improved over time, with is reflected both in the increase in notifications and in the demand for health care [40]. These are important limitations, as they were not considered in the present study.

Second, we did not consider data regarding the notification of scorpion species in SP. These data have recently been registered in a system created by the Endemic Diseases Department (SUCEN), a section of the São Paulo State Department of Health, to monitor these arthropods in the state. This system identifies both notifications and captures of scorpions by municipal technicians in real-time, and provides the geographical distribution of the species present throughout the state, generating indicators that are useful for the planning of municipal control and management activities related to scorpions [44].

There are several factors involved in epidemiology of scorpionism that could be futher explored to better understand this health problem: information about the scorpion population, environmental, demographic and socioeconomic conditions; climate change; accessibility to health care; and differences in the scorpion control methods and the management of scorpion stings by the municipalities; among others. Even though we previously discussed possible factors associated with scorpion envenomation, it is a limitation of the present study the fact that we do not consider these factors in our analysis.

The primary strength of our study is the use of spatial analysis techniques to map scorpion stings and detect at-risk areas. For mapping, we utilized the local empirical Bayesian rate to control random fluctuations of data in areas with small populations. To detect clusters, Gi* [57] with FDR correction was used for multiple comparisons. This technique, which limits the possibility of finding false-positive results, is more precise in identifying real agglomerates [31, 58]. Another strength of the present study is the standardization of the rates according to age and sex. This is an important factor for avoiding confusion bias in studies due to population age differences. Furthermore, this technique is often not described in the literature when the local empirical Bayesian method is used [59].

The best of our knowledge, this is the first study to highlight the increasing magnitude of scorpionism in the state of SP. Future studies should investigate the environmental and climatic characteristics of the areas with high and low rates of scorpion stings, and model the incidence rates of scorpionism and scorpion occurrence using environmental, climatic, demographic, socioeconomic, and other municipatity-specific characteristics. Therefore, it is crucial to improve the surveillance and control of this growing health concern in SP. Although we did not consider these characteristics in the present study, it is an important first step in understanding the actual distribution of scorpionism in SP, and can serve as a basis for future studies.

Conclusions

The incidence and mortality rates of scorpion envenomations increased significantly from 2008 to 2018 in the state of SP. Although this increase in incidence occurred in almost all municipalities and regions of the state, the highest incidences were found in the western, northwestern, and northern regions. Incidence rates were higher for men, and increased with age; however, fatalities from envenomations were concentrated almost entirely in children 0–9 years old of age. The distribution of accidents found in SP, as well as the identification of areas of greater risk, can be used to identify priority areas for the development of surveillance and control plans, both at the regional and municipal level. This distribution could also be useful in assessing the suitability of the location of the reference units for the care of scorpion accidents in SP, and may also be useful for sizing antivenom serum needs. The findings of the present study can help health services make decisions to reduce contact with scorpions and avoid fatalities, especially among children.

Scorpionism data aggregated by municipality, year, sex and age group with local empirical Bayesian standardization and incidence rates.

(XLSX)

Click here for additional data file.

Boxplot of local standardized empirical Bayesian rates (per 10,000 inhabitant-years) by year for all municipalities of the state of São Paulo, Brazil.

(TIF)

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26 Dec 2021

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4.  The reviewers appreciated the relevance of this study, since it focuses on an important public health issue in the state of Sao Paulo, i.e., the drastic increment in the incidence of envenomings by scorpion stings, a phenomenon that deserves analysis and attention by the research community and the public health system of the state. Reviewers highlighted a number of issues that should be carefully considered and taken into consideration for preparing a revised version of the manuscript.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: I Don't Know

Reviewer #3: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This study analyzed the historical series of scorpion stings in São Paulo, Brazil from 2008 to 2018 and occurrences in the 645 municipalities of this state.

Abstract:

1. "standardized by sex and age": change to "stratified by sex and age"

2. "the deaths were randomly distributed": randomly or proportional to incidence?

3. "Our findings that identify areas and populations at risk for scorpion envenomation and resulting fatalities can...": Change sentence. Suggestion: "In this study, we identified areas and population at risk for SE and associated-fatalities, which can..."

4. "...with these animals and avoid fatalities, especially in the most vulnerable population." Why mostly in the vulnerable population? Is it possible to conclude that from the results?

Introduction:

1. "Tityus is most medically relevant due to envenomations in children and high incidences in recent years." The other genera do not sting children? Strange sentence.

2. "Four species are epidemiologically important in Brazil: Tityus serrulatus, T. bahiensis, T. obscurus, and T. stigmurus." Sentence needs reference.

3. "Antivenin": Change to "antivenom" in the whole text.

4. "Antivenin is recommended for moderate and severe cases. [10, 13, 14]". Where? In Brazil? Accornding official guidelines?

5. "serious cases": change to "severe cases" in the whole text.

6. "at least minimize the sequelae and/or deaths". Sequelae? Which types?

7. "For this reason, it is extremely important 113 to characterize scorpion exposures in terms of victims as well as spatiotemporal factors." What 'in terms of victims' mean?

8. "This study consequently describes": Delete 'consequently'.

Methods

1. "scorpion exposures": change to "scorpion stings"in the whole text.

2. Include environmental and climate information in the Study area section.

3. "institutional ethics review board of the University of São Paulo School of Public Health (COEP FSP/USP, CAAE approval record 10457119.6.0000.5421, opinion 3408558)". Opinion?

Discussion:

"These authors showed that this increase is related to changes in temperature amplitude and is expected to be more pronounced in the north and northwest of the state, precisely the regions we found to be most affected."

I believe that the discussion about the greater incidence in the northern and northwestern regions of the state counties deserves further attention. What characteristics do these regions have that differentiate them from the rest of the state, in climatic and environmental terms, but also in terms of economic activities that they could include in contact with the scorpions? Different biomas? Are there studies on the density of these arthropods in the state? What do these works show for the regions with higher incidence? Different human development indexes?

Reviewer #2: The manuscript “Scorpion envenomation in the state of São Paulo, Brazil: Spatiotemporal analysis of a growing public health problem” by Lacerda et al. shows a dramatic increase in the incidence and mortality from scorpion envenomations between 2008 and 2018. The study aims to identify areas and populations at risk of scorpion envenomation and death in order to promote decision-making by the health services.

My main concern is that the authors do not sufficiently discuss the limitations of their study, especially with regard to the collection and analysis of data provided by the São Paulo State Epidemiological Surveillance Center.

The methodology is relevant and well described.

The results are aggregated, which does not allow a precise view of the data by group of people (sex, age), region and their evolution over time. Data confidentiality must be balanced for with more detailed analysis and comparisons.

The discussion raises 3 hypotheses – classic but convincing – about the causes of the increase in incidence and mortality, in particular the expansion of T. serrulatus which is gradually replacing T. bahiensis due to the new environmental conditions, and the evolution of human activities leading to both attraction of scorpions and increasing exposure. In this regard, the evolution of human activity is likely to be more strongly involved than climate change, the impact of which would be more gradual and could not explain, for example, the sudden increase in incidence and mortality from 2014.

However, as I indicated above, the authors do not sufficiently address other possible explanations such as the insufficient reporting of cases which would have improved between 2008 and 2018 or a gradual evolution of the healthcare seeking behavior of the patients (see Chippaux. J Venom Anim Toxins Incl Trop Dis. 2015; 21:13). They do not seek to verify these quite surprising results using data provided by independent sources.

Two ways should be considered to validate these hypotheses.

On the one hand, the authors indicate that the risk increased in all regions of the state of São Paulo throughout the study period. First, it is necessary to verify that the variables of interest show similar or even parallel evolutions in the different parts of the state and that there are no areas of significantly higher incidence and / or mortality which could be explained by variations in environmental conditions (scorpion population, human activities) and / or the management of scorpion stings (specially to prevent severe outcomes or death). There can be no convergence of epidemiological parameters (in particular parallelism of incidence in different places) in all the regions resulting from the authors' hypothesis insofar as the situations and their consequences cannot be identical in all the regions of the state of São Paulo. However, the authors indicate that the increase is higher (without data being available) in some regions. They should compare the explanatory situations (abundance of T. serrulatus, human activities, environmental and sanitary conditions, accessibility of health facilities, climate change) between different regions showing the highest differences in incidence (e.g. between the northwest, center and southern regions of the state of São Paulo).

On the other hand, the authors should check whether the increase in incidence and case fatality rate observed during the same period in randomly selected health centers in different regions is similar to that reported by the São Paulo State Epidemiological Surveillance Center.

I disagree with the authors when they state that underreporting of scorpion stings, especially mild cases, can be considered to occur uniformly in the state of São Paulo. The reasons for underreporting are not equivalent depending on the place and the person in charge of the case report. The case report may be affected by incidence, particularly frequency of mild or moderate envenomation, perception of the case severity, individual interest for the topic, overwork, etc...

Moreover, the authors do not seek to explain the increase in mortality, nor the random distribution of deaths between regions. They should study the case fatality rate of scorpion envenomation in a few hospitals located in areas with higher mortality. The increased case fatality rate could be related to difficulties in managing envenomation, e.g. failure of the antivenom supply or lack of knowledge of treatment of scorpion envenomation.

Assuming that the authors cannot answer some of these questions, they could at least mention and argue them.

Finally, the authors do not offer practical recommendations and let the health authorities make any decision based on their results. I think it's up to the authors to guide health authorities based on their results and knowledge of the problem.

Reviewer #3: The article addresses a very important issue related to scorpion injuries in Brazil, and also in other regions of the world, which has been increasing progressively year by year. The object of the study was the state of São Paulo, located in southeastern Brazil and which has 645 municipalities divided into 17 regional health districts, from 2008 to 2018. During this period there was an increase in the number of accidents of 425%. The aim of the study was to analyze the temporal and spatial distribution of the occurrence of accidents to identify areas of greater or lesser risk in order to develop strategies to reduce the population's contact with these scorpions to avoid deaths in the most vulnerable group (children 0-9 years of age).

The authors calculated the annual incidence and mortality rate standardized by sex and age. They used the empirical local Bayesian method and Gi* statistics to standardize the incidence rates in the municipalities and identify high and low risks of agglomeration.

There was a higher incidence and mortality among men, but mortality was concentrated in children under 9 years of age, with 42 of the total 48 deaths (88%) occurring in this group. From the analysis obtained by the maps, it was observed that accidents occurred more in the northern and northwestern regions of the state in contrast to the other regions, in addition to showing that the incidence of cases increased in all regions of S.Paulo.

The discussion about why this is happening was quite comprehensive, in terms of increased urbanization, climate effects, housing conditions, poverty, T. serrulatus parthenogenesis, etc.

**********

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Reviewer #1: No

Reviewer #2: Yes: Jean-Philippe Chippaux

Reviewer #3: Yes: Palmira Cupo

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3 Mar 2022

Dear editor,

We are submitting a second version of the manuscript entitled "Scorpion envenomation in the state of São Paulo, Brazil: Spatiotemporal analysis of a growing public health concern". We sent our manuscript to Editage for an English review and we accepted their suggestion to change our title (the old one was “Scorpion envenomation in the state of São Paulo, Brazil: Spatiotemporal analysis of a growing public health problem”). We have made substantial changes in the manuscript and have addressed the points raised by the reviewers. The changes are summarized below (in bold) to each reviewer's comment. We indicated the position (lines) of our modifications using the 'Revised Manuscript with Track Changes' version of our manuscript. We would like to thank the reviewers for their helpful comments and suggestions. We further thank you for your valuable time spared for our manuscript.

A - ANSWERS TO EDITOR

1 - The most important aspects to consider are:

(a) the need to make the data of the study publicly available, as per the policy of the journal,

Answer: We included the database as Supplementary Material 1 (S1 File).

(b) the need to discuss the limitations of the methodology used and the conclusions reached, and

Answer: We improve the discussion of the limitations of our study (lines 430-460 of Track Changes version; lines 388-410 of Manuscript version).

(c) the strengthening of the discussion by considering some aspects mentioned by the reviewers, such as the possible geographical differences within the state regarding incidence and mortality due to scorpion sting envenomings, and further exploring and discussing the hypothesis presented to explain the increment in the incidence of these accidents, among other points.

Answer: We improved our Discussion, taking into account these issues.

2 – Figures of our manuscript

Answer: We created the Figures 1, 3 and 5 (old Figure 4) using data and shapefiles from the Brazilian Institute of Geography and Statistics (IBGE) and the Brazilian Information System for Notifiable Diseases (SINAN). This information is of free and open accesses for everyone. So the maps we use in our manuscript, since they are freely accessible, are not copyrighted. Moreover, these maps were created using the Free and Open Source QGIS.

B - ANSWERS TO REVIEWERS

Reviewers' comments:

III.1 - Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Yes

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: I Don't Know

Reviewer #3: Yes

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes

Answer: We made our data available in the Supplementary Material 1 (S1 File).

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

Answer: We made the English correction suggested by the Reviewers and also sent our manuscript to Editage for an English review. We attached the certificate of this review in the submission system.

III.2 - Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

A - Reviewer #1: This study analyzed the historical series of scorpion stings in São Paulo, Brazil from 2008 to 2018 and occurrences in the 645 municipalities of this state.

Abstract:

1. "standardized by sex and age": change to "stratified by sex and age"

Answer: Ok, we corrected this (line 35).

2. "the deaths were randomly distributed": randomly or proportional to incidence?

Answer: According to our results, we did not see a directly correspondence between the deaths and the incidence rates, since the deaths occurred in all areas (high, median and low incidence rates). Then, we maintained the text in its original presentation.

3. "Our findings that identify areas and populations at risk for scorpion envenomation and resulting fatalities can...": Change sentence. Suggestion: "In this study, we identified areas and population at risk for SE and associated-fatalities, which can..."

Answer: We accepted this suggestion and changed our text (lines 49-53 of Track Changes version; lines 47-50 of Manuscript version).

4. "...with these animals and avoid fatalities, especially in the most vulnerable population." Why mostly in the vulnerable population? Is it possible to conclude that from the results?

Answer: We found that the most vulnerable population are the 0 to 9 years old children, with the highest mortality rates. We changed the text to “…with these arachnids and avoid fatalities, especially in children.” (lines 52-53 of Track Changes version; lines 49-50 of Manuscript version).

Introduction:

1. "Tityus is most medically relevant due to envenomations in children and high incidences in recent years." The other genera do not sting children? Strange sentence.

Answer: We changed the text to “Tityus is most medically relevant scorpion genus due to clinical manifestations caused by envenomations in human and the high incidence in recent years." (lines 70-72 of Track Changes version; lines 67-69 of Manuscript version).

2. "Four species are epidemiologically important in Brazil: Tityus serrulatus, T. bahiensis, T. obscurus, and T. stigmurus." Sentence needs reference.

Answer: We inserted two references about this issue (line 74 of Track Changes version; line 71 of Manuscript version).

3. "Antivenin": Change to "antivenom" in the whole text.

Answer: We changed the term “antivenin” to “antivenom” in the whole text.

4. "Antivenin is recommended for moderate and severe cases. [10, 13, 14]". Where? In Brazil? Accornding official guidelines?

Answer: We include the following phrase to explain better this issue: “According to the Brazilian Ministry of Health Guidelines, antivenom treatment is recommended in which the patient presents with signs and symptoms of systemic envenomation, which are classified as moderate or severe cases depending on the severity of the clinical manifestations.” (lines 87-91 of Track Changes version; lines 81-85 of Manuscript version).

5. "serious cases": change to "severe cases" in the whole text.

Answer: We changed the term “serious” to “severe” in the whole text.

6. "at least minimize the sequelae and/or deaths". Sequelae? Which types?

Answer: We changed the text to “at least minimize the risk of death due to an envenomation.” (lines 105-106 of Track Changes version; lines 97-98 of Manuscript version).

7. "For this reason, it is extremely important to characterize scorpion exposures in terms of victims as well as spatiotemporal factors." What 'in terms of victims' mean?

Answer: We changed the text to "For this reason, it is extremely important to characterize scorpion envenomations in terms of the people affected by scorpion stings, as well as, spatiotemporal factors." (lines 106-109 of Track Changes version; lines 98-100 of Manuscript version).

8. "This study consequently describes": Delete 'consequently'.

Answer: Ok we corrected this (line 115 of Track Changes version; line 105 of Manuscript version).

Methods

1. "scorpion exposures": change to "scorpion stings" in the whole text.

Answer: We did this in the whole text.

2. Include environmental and climate information in the Study area section.

Answer: We included a new paragraph (2nd paragraph of the Methods) to deal with this issue. We changed the Figure 1, including the relief of the state of São Paulo to better explain its climate information (lines 131-145 of Track Changes version; lines 120-134 of Manuscript version).

3. "institutional ethics review board of the University of São Paulo School of Public Health (COEP FSP/USP, CAAE approval record 10457119.6.0000.5421, opinion 3408558)". Opinion?

Answer: We change ‘opinion’ to ‘protocol number’ (line 193 of Track Changes version; line 176 of Manuscript version).

Discussion:

"These authors showed that this increase is related to changes in temperature amplitude and is expected to be more pronounced in the north and northwest of the state, precisely the regions we found to be most affected."

I believe that the discussion about the greater incidence in the northern and northwestern regions of the state counties deserves further attention. What characteristics do these regions have that differentiate them from the rest of the state, in climatic and environmental terms, but also in terms of economic activities that they could include in contact with the scorpions? Different biomas? Are there studies on the density of these arthropods in the state? What do these works show for the regions with higher incidence? Different human development indexes?

Answer: We formed a team to study the scorpions and their accidents in the state of São Paulo and to do propositions to improve the surveillance and control of this growing health problem in our state. The team includes technicians and researchers of the São Paulo State Epidemiological Surveillance Center (CVE), Butantan Institute, and Endemic Diseases Department (SUCEN), which are sections of the São Paulo State Department of Health. This team also includes people of the School of Public Health of the University of São Paulo and of the Department of Health of the Municipality of Santa Bárbara d’Oeste, state of São Paulo. This manuscript is one of the first to be produced and we are conducting other studies where we are investigating the environmental and climatic characteristics of the cluster of high and low rates of scorpion stings in of the state of São Paulo, and modelling the incidence rates of scorpionism and the scorpion occurrence using environmental, climatic, demographic, socioeconomic and other characteristics of the municipalities of our state. Since we had a broad list of goals in the present manuscript and we are preparing other manuscripts, we considered that it would not be productive or viable to include results related to covariates associated to the scorpionism. On the other hand, we did not fail to present, in our discussion section, the factors possibly associated with the phenomenon studied. We changed our Discussion to deal better with these issues. We also included a new paragraph at the end of the Discussion about future studies and the need to investigate the factors associated with the scorpion stings and the scorpion infestation (lines 471-479 of Track Changes version; lines 421-429 of Manuscript version).

B - Reviewer #2 – Dr. Jean-Philippe Chippaux: The manuscript “Scorpion envenomation in the state of São Paulo, Brazil: Spatiotemporal analysis of a growing public health problem” by Lacerda et al. shows a dramatic increase in the incidence and mortality from scorpion envenomations between 2008 and 2018. The study aims to identify areas and populations at risk of scorpion envenomation and death in order to promote decision-making by the health services.

1 - My main concern is that the authors do not sufficiently discuss the limitations of their study, especially with regard to the collection and analysis of data provided by the São Paulo State Epidemiological Surveillance Center.

Answer: We rewrote and expanded the text about the limitations of our study (lines 430-460 of Track Changes version; lines 388-410 of Manuscript version).

2 - The methodology is relevant and well described.

Answer: Thank you for recognizing the relevance of the Methods of our manuscript.

3 - The results are aggregated, which does not allow a precise view of the data by group of people (sex, age), region and their evolution over time. Data confidentiality must be balanced for with more detailed analysis and comparisons.

Answer: We included a new figure (Figure 4 – its title is on lines 264-267 of Track Changes version; lines 242-245 of Manuscript version) that presents the evolution of the scorpion stings incidence rates from 2008 to 2018 for the 17 Regional Health Districts (RHDs) of the state of São Paulo. In addition to detailing the presentation of the incidence rates of scorpion envenomations according to regions of the state, another motivation is to show that the increase of the incidence rates occurred in almost all regions. This also happened with the municipalities, as it is possible to see in the Supplementary Material 2 that we included in this new version. Table 1 presents the scorpion envenomation for groups of people by sex and age. Figure 1 presents the temporal evolution of the incidence and mortality rates of scorpion stings for the state of São Paulo during 2008 to 2018.

4 – The discussion raises 3 hypotheses – classic but convincing – about the causes of the increase in incidence and mortality, in particular the expansion of T. serrulatus which is gradually replacing T. bahiensis due to the new environmental conditions, and the evolution of human activities leading to both attraction of scorpions and increasing exposure.

4.1 - In this regard, the evolution of human activity is likely to be more strongly involved than climate change, the impact of which would be more gradual and could not explain, for example, the sudden increase in incidence and mortality from 2014. However, as I indicated above, the authors do not sufficiently address other possible explanations such as the insufficient reporting of cases which would have improved between 2008 and 2018 or a gradual evolution of the healthcare seeking behavior of the patients (see Chippaux. J Venom Anim Toxins Incl Trop Dis. 2015; 21:13). They do not seek to verify these quite surprising results using data provided by independent sources.

Answer: We agree with this observation and included a new paragraph in the Discussion to deal with these issues (3rd paragraph of Discussion section – lines 325-339 of Track Changes version; lines 294- 308 of Manuscript version). Thank you for the indication of this paper.

4.2 - Two ways should be considered to validate these hypotheses.

On the one hand, the authors indicate that the risk increased in all regions of the state of São Paulo throughout the study period. First, it is necessary to verify that the variables of interest show similar or even parallel evolutions in the different parts of the state and that there are no areas of significantly higher incidence and / or mortality which could be explained by variations in environmental conditions (scorpion population, human activities) and / or the management of scorpion stings (specially to prevent severe outcomes or death). There can be no convergence of epidemiological parameters (in particular parallelism of incidence in different places) in all the regions resulting from the authors' hypothesis insofar as the situations and their consequences cannot be identical in all the regions of the state of São Paulo. However, the authors indicate that the increase is higher (without data being available) in some regions. They should compare the explanatory situations (abundance of T. serrulatus, human activities, environmental and sanitary conditions, accessibility of health facilities, climate change) between different regions showing the highest differences in incidence (e.g. between the northwest, center and southern regions of the state of São Paulo).

On the other hand, the authors should check whether the increase in incidence and case fatality rate observed during the same period in randomly selected health centers in different regions is similar to that reported by the São Paulo State Epidemiological Surveillance Center.

I disagree with the authors when they state that underreporting of scorpion stings, especially mild cases, can be considered to occur uniformly in the state of São Paulo. The reasons for underreporting are not equivalent depending on the place and the person in charge of the case report. The case report may be affected by incidence, particularly frequency of mild or moderate envenomation, perception of the case severity, individual interest for the topic, overwork, etc...

Moreover, the authors do not seek to explain the increase in mortality, nor the random distribution of deaths between regions. They should study the case fatality rate of scorpion envenomation in a few hospitals located in areas with higher mortality. The increased case fatality rate could be related to difficulties in managing envenomation, e.g. failure of the antivenom supply or lack of knowledge of treatment of scorpion envenomation.

Assuming that the authors cannot answer some of these questions, they could at least mention and argue them.

Answer: We included two figures in this new version of our manuscript. Figure 4 (its title is on lines 264-267 of Track Changes version; lines 242-245 of Manuscript version) shows that the increase of the incidence rates of scorpion stings occurred in almost all Regional Health Districts (RHDs) of the state of São Paulo. We also introduced a Figure, as Supplementary Material 2 (S2 Fig), showing that the increase in the incidence rates occurred, similar to what happened with the regions, in almost all municipalities of the state. Even revealing that this increase was a widespread phenomenon in the state, the methods we used (Local empirical Bayesian method and Getis-Ord Gi*) showed that it was more pronounced in the western, northwestern, and northern regions of SP, with significant high risk clusters.

We agree that there are several factors involved in the scorpionism epidemiology that could be explored to better understand this important public health, as the factors cited in this review. We discussed part of them, but did not take them into account in our analysis. So that, we considered this another limitation of our study (lines 453-460 of Track Changes version; lines 403-410 of Manuscript version). Nonetheless, we are conducting new studies considering these factors in our analysis. As we had pointed out to the Review # 1, we formed a team to study the scorpions and their accidents in SP and to do propositions to improve the surveillance and control of this important health problem in our state. The team includes technicians and researchers of the São Paulo State Epidemiological Surveillance Center (CVE), Butantan Institute, and Endemic Diseases Department (SUCEN), which are sections of the São Paulo State Department of Health. This team also includes technicians and researchers of the School of Public Health of the University of São Paulo and of the Department of Health of the Municipality of Santa Bárbara d’Oeste, state of São Paulo. This manuscript is one of the first to be produced and we are conducting other studies where we are investigating the environmental and climatic characteristics of the cluster of high and low rates of scorpion stings in of the state of São Paulo, and modelling the incidence rates of scorpionism and the scorpion occurrence using environmental, climatic, demographic, socioeconomic and other characteristics of the municipalities of our state.

We agreed with the reviewer about our statement that underreporting of scorpion stings, especially mild cases, can be considered to occur uniformly in the state of São Paulo and remove this text of the Discussion section.

4.4 - Finally, the authors do not offer practical recommendations and let the health authorities make any decision based on their results. I think it's up to the authors to guide health authorities based on their results and knowledge of the problem.

Answer: We included these recommendations in the Conclusions (lines 492-499 of Track Changes version; lines 437-444 of Manuscript version).

Reviewer #3 – Dr. Palmira Cupo: The article addresses a very important issue related to scorpion injuries in Brazil, and also in other regions of the world, which has been increasing progressively year by year. The object of the study was the state of São Paulo, located in southeastern Brazil and which has 645 municipalities divided into 17 regional health districts, from 2008 to 2018. During this period there was an increase in the number of accidents of 425%. The aim of the study was to analyze the temporal and spatial distribution of the occurrence of accidents to identify areas of greater or lesser risk in order to develop strategies to reduce the population's contact with these scorpions to avoid deaths in the most vulnerable group (children 0-9 years of age).

The authors calculated the annual incidence and mortality rate standardized by sex and age. They used the empirical local Bayesian method and Gi* statistics to standardize the incidence rates in the municipalities and identify high and low risks of agglomeration.

There was a higher incidence and mortality among men, but mortality was concentrated in children under 9 years of age, with 42 of the total 48 deaths (88%) occurring in this group. From the analysis obtained by the maps, it was observed that accidents occurred more in the northern and northwestern regions of the state in contrast to the other regions, in addition to showing that the incidence of cases increased in all regions of S.Paulo.

The discussion about why this is happening was quite comprehensive, in terms of increased urbanization, climate effects, housing conditions, poverty, T. serrulatus parthenogenesis, etc.

Answer: Thank you for your comments and for considering our study suitable and important.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

15 Mar 2022

Scorpion envenomation in the state of São Paulo, Brazil: Spatiotemporal analysis of a growing public health concern

PONE-D-21-37124R1

Dear Dr. Lacerda,

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Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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Reviewer #2: Yes

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Reviewer #2: Yes

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Reviewer #2: Yes

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Reviewer #1: I recommend to accept as it is in this new version.

I recommend to accept as it is in this new version.

Reviewer #2: The revision of the article "Scorpion envenomation in the state of São Paulo, Brazil: Spatiotemporal analysis of a growing public health concern" by Lacerda et al. shows clear improvements. The remarks and suggestions I had made on the previous manuscript were all taken into account in the revised version. In my opinion, the paper can be published as is.

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Reviewer #1: No

Reviewer #2: Yes: Jean-Philippe Chippaux

31 Mar 2022

PONE-D-21-37124R1

Scorpion envenomation in the state of São Paulo, Brazil: Spatiotemporal analysis of a growing public health concern

Dear Dr. Lacerda:

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