Epidemiological characterization and spatial distribution of visceral leishmaniasis cases in Três Lagoas-MS, Brazil in the period of 2007-2021

This retrospective observational cross-sectional study aimed to analyze the distribution of visceral leishmaniasis (VL) cases in Três Lagoas registered between January 2007 and August 2021, through data processed by the Epidemiological Surveillance Service based on the notification of the National System of Diseases and Notifications. In this period, 231 cases were confirmed, being 137 male (59.3%) and 94 female (40.7%). Was observed a higher prevalence of cases between ages 0-4 years (30.8%), 20-39 (22.5%) and 40-59 (19.9%). Also was observed a higher percentage of infected Caucasian individuals (45.4%) and individuals with low education: elementary school II (22.1%). The most prevalent clinical manifestations were fever (85.3%), splenomegaly (76.6%), weakness (67.1%), weight loss (65.8%) and hepatomegaly (62.8%). It was found that 80.1% of patients received pharmacological treatment, mainly using pentavalent antimonials (56.7%), and that 26 patients (11.3%) died during the period due to complications caused by VL. The spatial analysis showed a homogeneous distribution of VL cases in the city's urban perimeter without predominant regions. Finally, it was observed that the incidence and mortality by VL has been decreasing in recent years, however maintaining high rates of lethality and transmissibility, placing the municipality in the third with the highest transmission rate in the state. In view of these aspects, we conclude that VL is still a serious public health problem in the city and that despite the slight drop in incidence and mortality rates, it still presents values higher than the national average and high dissemination of the disease in the urban area.


Introduction
Visceral Leishmaniasis (VL) is a vector disease that affects humans and other animals, with chronic evolution and systemic involvement that can lead to death. This disease is considered by the World Health Organization as one of the five neglected diseases, that encouraging its extinction. Although there are asymptomatic forms of the disease, when patient develops little or no specific symptoms, VL can chronically evolve with high mortality rates when untreated, mainly affecting organs such as the spleen, liver, hemocytopoietic tissue, lungs and kidneys (Souza et al., 2018).
The symptoms may appear abrupt or gradual, like the hepatosplenomegaly, prolonged and irregular fever, anemia with leukopenia, lymphadenopathy, edema, weight loss and cachexia. The time to diagnosis is closely related to the threat of transmission, as the host is at risk of acting as a reservoir. In order to control and treat patients affected by VL in Brazil, all suspected cases need to be notified through a specific form to the Notifiable Diseases Information System (SINAN), it will be responsible for the epidemiological investigation of the case (Brazil, 2019;Carvalho et al., 2018;Brazil 2016).
It is still possible to observe worldwide incidence ranging from 50 to 90 thousand cases annually, being endemic in more than 80 countries, among which the following stand out: Brazil, China, India, Iraq, Ethiopia, Kenya, Nepal, Sudan, South Sudan and Somalia, responsible for about 95% of cases worldwide (WHO, 2020;Bezerra et al., 2018). Brazil is the country that most reports cases in America, and approximately 96% of cases, mainly due to social, economic and environmental characteristics favorable to the proliferation and spread of mosquito vectors (PAHO 2018; Araújo et al., 2013;Lara-Silva et al., 2015). Research, Society andDevelopment, v. 10, n. 16, e72101623258, 2021 (CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10.33448/rsd-v10i16.23258 3 The prevalence of VL in Brazil ranged from 1.2 to 1.98 cases per 100,000 inhabitants, in the last decade (2010 to 2019).
In 2019 was registered the highest fatality rate (9%) in the last 10 years. In the same year were confirmed autochthonous cases of VL in 24 Brazilian states (88.9%), distributed in all 5 regions of the country. The Northeast region was responsible for the largest number of case records in the country, with 49.1% of cases, followed by the North region (19.98%) and the Southeast region (12.77%) (Brazil, 2019;Brazil, 2021). In 2019 the Midwest region was responsible for 5.1% of VL cases in the country.
The state of Mato Grosso do Sul (MS) was responsible for 75.3% of cases in this region, placing the state in eighth position in number of cases, and fifth in overall incidence, with 3.5 cases per 100,000 inhabitants (Brazil, 2019;Brazil, 2021). Therefore, it was observed that VL has been expanding in some urban areas of the state, including Três Lagoas, with a transmission rate of 13.4 in the period 2014 to 2019, only behind Campo Grande (85.8%) and Corumbá (13.6%). In addition, the municipality ranks second in number of deaths from VL, only behind of Campo Grande, which has encouraged prioritizing disease control and surveillance activities (SES -MS, 2020).
The action plan for leishmaniasis on the American continent was created and approved in 2017. It has purposed the reduction of the morbidity and mortality of the LV, as well as to assist in the diagnosis and treatment strategies, aiming the control of the disease until the year 2022.
Epidemiological analyzes using geographic distribution techniques as well as analysis of spatial patterns of morbidity and/or mortality; socioeconomic and environmental factors can provide important information to contribute with the prevention and control of the VL. Thus, this study aimed to analyze, to characterize epidemiologically and describe the spatial distribution of cases of visceral leishmaniasis in Três Lagoas, state of MS, from 2007 to 2021.

Methodology
A retrospective, observational cross-sectional study of confirmed and autochthonous VL cases in the city of Três Lagoas, from 2007 to August 2021, was carried out. Data were collected from SINAN and from the department of epidemiological surveillance, being grouped and tabulated in the Excel software.
Analysis the data were grouped into three periods: 2007-2011, 2012-2016 and 2017-2021. The following demographic variables were analyzed: gender (male and female); age group (in years: 0-4; 5-9; 10-19; 20-39; 40-59; ≥60); ethnicity (Caucasian, afro-descendant, asian, mulatto, indigenous); education (illiterate, elementary school I, elementary school II, high school, higher education); treatment (Pentavalent antimony, amphotericin B, pentamidine, liposomal amphotericin B, other or untreated) and disease evolution (Cure, abandonment, death from VL, death from other causes and ignored or untreated). In addition, the frequency of clinical manifestations of VL recorded in each case, such as fever, weakness, weight loss, splenomegaly, hepatomegaly, edema, hemorrhagic phenomena, jaundice, cough, were also studied. The cases that progressed to death were characterized separately according to the variables used in the study.
Spatial distribution was performed through the making of thematic maps, separated by neighborhoods (district zoning model 2015 containing 36 neighborhoods) showing the number of total cases in each neighborhood. Similarly, thematic maps were constructed showing the number of deaths per neighborhood, and another map showing the lethality by neighborhood, the latter being categorized into intervals (<10% lethality; 11-20% lethality; 21 -30% lethality and 31-40% lethality) for the total period analyzed. All the maps were made with the program ArcGIS 10.8 (Esri -USA).
The incidence of each year was calculated by dividing the total number of cases in the year by the population at risk, multiplied by 100,000 inhabitants. To calculate the mortality rate, the number of deaths in one year was divided by the number of people at risk, multiplied by 100,000 inhabitants. Finally, to determine the lethality, the number of deaths in the year was divided by the number of cases in the same period, multiplied by 100. Subsequently, averages of these incidences were performed covering the grouped periods.

Results
From January 2007 to August 2021, 1192 suspected cases of VL were reported, with 231 confirmed cases (19.4%) and 26 deaths (11.3%). There was a predominance of cases in males (59.3%) during the epoch analyzed. A higher percentage in man was observed in the period 2007-2011 (61%) and a lower percentage, from 2012 to 2016 (54.3%), however, were not observed statistically significant differences. Analyzing the age groups, there was a greater predominance between 0-4 years old (30.8%), followed by 20-39 years old (22.5%) in the analysis of the total period, separately, it was observed that the 20-39 age group had a higher proportion of new cases during the period 2017-2021 (34.1%) ( Table 1).
The analysis of the predominance in different ethnicities showed a higher percentage of cases in Caucasians (45.4%), is highlighted, mainly due to cases in the age group of 0-4 years old (not applied) and the lack of filling in the data (ignored).
Still, was verified a lower prevalence of cases in illiterate individuals (0.9%) and people with higher education (3%), without statistical significance (Table 1).
About the most prevalent clinical manifestations: fever was present in 85.3% of patients throughout the period, 80.9% hepatomegaly (62.8%) were also frequently observed in all periods. Interestingly, the cough was observed in more than 50% of patients throughout the period, ranging from 45.5% in 2017-2021 to 52.2% in 2012-2016. Among the clinical manifestations with less predominance, we had hemorrhagic phenomena (6.1%), jaundice (18.2%) and edema (24.2%) ( Table 1).
The most frequently used treatment was Pentavalent Antimonial (56.7%), followed by Amphotericin B (13%) and Liposomal Amphotericin (9.5%), however, in the period 2017-2021, Liposomal Amphotericin was the second drug most used  (Table 1).  The analysis of deaths from VL showed a predominance in males (53.8%), however in the periods 2012-2016 and 2017-2021, the percentage of deaths in women was higher (57.1%). It was observed that the age group 40-59 years concentrated the highest number of deaths from VL (34.7%), followed by >60 (26.9%) and 0-4 (19.3%) . Still, it was found that 84.6% of these patients who died from VL underwent pharmacological treatment, being the most used: Pentavalent Antimonial (34.6%), Amphotericin B (26.9%) and Liposomal Amphotericin (23.1%) ( Table 2). The statistical analysis did not show statistical significance for the differences in the percentage of deaths by sex, age or pharmacological treatment.
The spatial distribution of deaths from VL, in the period 2007-2021, showed that 15 urban neighborhoods (41.7%) had at least one confirmed death from VL with distribution in a central area ranging from the northeast to the southwest of the city.
Deaths from VL were also registered in the rural area in quantity similar to those found in the urban region ( Figure 2). The spatial distribution of the percentage of lethality by neighborhood, in the period 2007-2021 was analyzed and observed an emphasis on three more peripheral neighborhoods, which presented a lethality percentage ranging from 31 to 40% (Figure 2).
The analysis of the incidence of VL showed, in the period 2007-2011, an average incidence of 30.8 cases per 100,000 inhabitants, with a maximum incidence in 2008 (63.2 cases per 100,000 inhabitants) and a minimum in the year of 2011 (9.6 cases per 100,000 inhabitants). In the subsequent period (2012-2016) there was a decrease in this average incidence (8.2 cases per 100,000 inhabitants), minimum incidence in 2013 (3.7 cases per 100,000 inhabitants) and maximum in 2016 (10.3 cases per 100,000 inhabitants), with statically relevant decrease (p=0.0003). In the period (2017-2021) there was a further decrease in the average incidence (6.7 cases per 100,000 inhabitants), a minimum incidence in 2020 (2.4 cases per 100,000 inhabitants) and maximum in the year 2017 (12.7 cases per 100,000 inhabitants). Not observed statistical significance when compared to the previous period (2012-2016), however was observed statistical significance when compared to the 2007-2011 period (p<0.0001).
The average mortality rate from VL in the period 2007-2011 was determined at 2.5 cases per 100,000 inhabitants, a maximum mortality rate in 2008 (4.5 cases per 100 thousand inhabitants) and a minimum in 2007 (1.2 cases per 100,000 inhabitants). In the following period (2012-2016), there was a decrease in the average mortality rate (1.3 cases per 100,000 inhabitants), with a minimum mortality in the years 2014, 2015 and 2016 (0.9 cases per 100,000 inhabitants) and maximum in 2012 (1.9 cases per 100,000 inhabitants), but without statistical significance. In the period from 2017 to 2021, there was a decrease in the average mortality rate (1.0 cases per 100,000 inhabitants). The maximum mortality rate was observed in 2019 (2.5 cases per 100,000 inhabitants) and minimum in 2020 (no deaths registered), without statistical significance.

Discussion
The datas showed a reduction of VL in the analyzed periods, especially in the incidence and mortality; however, the city of Três Lagoas is ranked as the third municipality with the highest VL transmission rate in the state of Mato Grosso do Sul, subsequently Campo Grande and Corumbá (SES -MS, 2020). In addition, the average incidence found in the period with the lowest number of cases (2017-2021) is considered high equaling those found in the north and northeast regions, where VL has the highest incidence (Araújo, 2017) It was observed that almost 60% of VL cases in the city occurred in male individuals, maintaining this percentage in all evaluated periods. Studies on the incidence of VL in other cities in the country also point to a greater susceptibility of men to the disease, with a percentage between 58 and 75% of cases (Rodrigues et al., 2020;Souza et al., 2018;Rocha et al., 2018;Lisboa et al., 2016;Araújo, 2016;Ortiz et al., 2015). It is considered that the greater exposure of men to sources of contamination, due to the performance of occupational and behavioral activities as well as hormonal factors are responsible for this higher percentage of infection (Ortiz et al., 2015). Furthermore, studies show that sex hormones can influence the immune response causing greater infectivity, prevalence and clinical severity in men (Araújo Albuquerque et al., 2021).
The classification of VL cases by age groups showed the highest total percentage in children aged 0-4 years (30.8%), followed by 20-39 years (22.5%) and 40-59 years (19.9%). Corroborating these results, an epidemiological study of VL in the city of Bauru -SP found that 32.3% of cases occurred in children under 5 years of age, and another study in Fortaleza -CE from 2009 to 2013 showed that 31.5 % of cases occurred in this same age group (Ortiz et al., 2015;Rodrigues et al., 2017). However, a new study in the city of Fortaleza -CE, showed that from 2014 to 2017, the percentage of cases in this age group decreased considerably (13.1%), with cases in the 20-39 age group being concentrated. (33.2%) and 40-59 years (32.4%) . The greater susceptibility and severity of VL in young children can be explained by the relative immaturity of the immune system, especially the adaptive cellular immune system, which is further aggravated by factors such as malnutrition (Pérez-Cabezas et al., 2019;Gama et al., 2013;Ostyn et al., 2011). The abundant presence of the vector mosquito in urban areas, especially in the surroundings regions, exposes this population to VL .
The most predominant ethnicity among VL cases in the city was Caucasian (45.4%), followed by mulatto (39%) when analyzed throughout the study period, but in the 2012-2016 periods and 2017-2021 the highest percentage of cases was in mulatto (58.7% and 50% respectively). Although other studies corroborate a higher prevalence in Caucasian (Ortiz et al., 2015) or in mulatto (Souza et al., 2018;Lisboa 2016;Batista et al., 2013). We hypothesized that this characteristic is due to the ethnic particularity of the population of the municipality.
In the city, VL was more frequent in individuals with low education, elementary II (22.1%) and elementary I (17.3%).
This predominance is habitually observed in epidemiological studies of VL in different cities across the country, corroborating the findings of this study (Souza et al., 2018;Lisboa et al., 2016;Ortiz et al., 2015). The relationship of low education and conditions of economic vulnerability in individuals affected by VL is quite frequent, however, there is a high percentage of people classified as ignored or not applied, these being young children (before starting school life) and individuals who information had not collected. Still, there is a low percentage of cases of illiterate individuals (0.9%), and this characteristic is explained as a particularity of the city, which has low illiteracy rates in the population.
Interestingly, cough was observed in over half of patients, similar with that one found by Almeida et al. (2020). This phenomenon is explained by the thoracoabdominal organ compromising, causing greater abdominal volume, responsible for adaptations in respiratory mechanics, which can trigger respiratory symptoms such as dyspnea and cough Bispo et al., 2020).
Between 2008 and 2017, the mortality rate from VL has been increasing across the country (6.2% to 8.8%) and in the municipality of Três Lagoas, it was no different. Was observed a growing percentage of death in periods (2007-2011: 8.5%; 2012-2016: 15.2%; 2017-2021: 15.9%) which led to an average lethality of 11.7% (2007-2011); 19.6% (2012-2016) and 14.5% (2017-2021), representing rates well above those found in the analysis of the average lethality in the country (Brasil, 2017). VL cure rates in the city were above 80%, similar to that found by Almeida et al. 2020 (78.2%) in a study carried out in Fortaleza -CE and slightly higher than the reported in Latin America in 2016 (70%) and 2017 (71.3%) (PAHO, 2019).
Mortality from VL in the city was higher in men (53.8%), when analyzed throughout the study period (2007)(2008)(2009)(2010)(2011)(2012)(2013)(2014)(2015)(2016)(2017)(2018)(2019)(2020)(2021), but in the periods 2012-2016 and 2017-2021 the percentage of women was higher, with 57,1% in both periods. Botelho and Natal (2009), analyzing the epidemiological profile of VL in Campo Grande -MS, showed that 75% of deaths occurred in men, which is corroborated by Ortiz and Anversa (2015) who demonstrated that 61.3% of deaths for VL occurred in Bauru -SP were in men. The large number of infected men, leading to a higher percentage of mortality, could be relation with hormonal factors that can regulate and influence by the immune response, responsible for control of the levels of mast cells, eosinophils, macrophages and dendritic cells (Araújo Albuquerque et al., 2021). Liu et al. (2005 and demonstrated that testosterone could give rise to the increase of susceptibility to the infection, inducing apoptosis, immunosuppression, attenuation of MAPK signaling and increased the disease. In a study carried out in 2016 in India, it was observed that testosterone could increase the anti-inflammatory microenvironment and favor the persistence of the parasite (Mukhopadhyay et al., 2016).
Deaths from VL were concentrated primarily in the ages 40-59 years (34.7%) and >60 years (26.9%), followed by those under 4 years (19.3%). These data are corroborated by national data on deaths and mortality by age group between 2008 and 2017, which show a higher percentage of deaths in individuals over 50 and under 4 years of age. Studies suggest that the highest percentage of deaths in these extreme ages is mainly due to the immaturity of the immune system in childhood, and the decreased efficiency of the immune system (immunosenescence), compromising, in both, mainly the cellular immune response (Pérez-Cabezas et al., 2019;Gama et al., 2013;Ostyn et al., 2011). It should be noted that 84.6% of the individuals who died had undergone some pharmacological treatment, but despite the efficiency of the drugs, the emergence of resistant strains, the delay in diagnosis/treatment, adverse effects and other comorbidities presented by patients, may be responsible for the mortality of these individuals (Santiago et al., 2021;Jha et al., 2013;Sundar et al., 2010).
Unlike what was found by Almeida et al. (2020), who showed a greater prevalence of cases in neighborhoods on the outskirts of Fortaleza -CE and neighborhoods with low socioeconomic status and deficient urban infrastructure, VL cases in the city showed a homogeneous distribution in different urban neighborhoods and rural with 75% of neighborhoods presenting at least one case of VL. This homogeneous distribution of cases can be explained from a study carried out by Oliveira et al. (2010) in Três Lagoas, where the circulation of sandflies was evaluated, showing that 86.8% of the monitored neighborhoods showed circulation of sandfly species., mainly in the intra and peri domiciliary environment (88.4%). The neighborhoods with the highest number of human cases of VL are also those with the highest detection of sandfly species, mainly of the genus Lutzomyia spp.
The distribution of the percentage of deaths and lethality by neighborhood was homogeneous, with slightly higher lethality and deaths in more peripheral neighborhoods of the city, corroborating what was observed by Almeida et al. (2020), which showed that peripheral neighborhoods with infrastructure and sanitation problem may be more susceptible to VL cases.
Finally, this study shows the epidemiological situation of VL in Três Lagoas, in last 15-year (2007-2021), and despite oh having used secondary data (SINAN and the municipality's Epidemiological Surveillance Secretariat), which may present some inaccuracy, the study allowed an overview of VL in the city, which can help in decision-making and policies to deal with the disease.

Conclusion
We conclude that there was a decrease in the incidence and mortality of VL, during the analyzed periods. However, Três Lagoas-MS still presents the incidence and mortality well above the national average. Despite the decrease in these rates over the years, it was found that municipality had high rates of transmission and cases of VL, what kept the city as one of the three municipalities with the highest transmission rate in the Mato Grosso do Sul. It showed an increase in the percentage of lethality, higher averages than those found at the national level. Finally, we conclude that the city has a homogeneous distribution of VL cases in all neighborhoods. With that, suggest that prophylactic measures and health education should be carried out throughout the city in order to reduce the percentage of new cases. All these data corroborate the classification and maintenance of the city as an endemic area for visceral leishmaniasis.