Temporal trend in the incidence of human visceral leishmaniasis in Brazil

Abstract It is an ecological study that analyzed the time trend of visceral leishmaniasis incidence rates in Brazil using segmented time regression by joinpoints. There was a decreasing incidence rate of this disease in the country with an average annual percent change (AAPC) of -5 (CI95%: -9.1; -0.6) and a reduction of 1.69 cases/100 thousand inhabitants in 2007, and 0.91/100 thousand inhabitants in 2020. The Central-West region showed the highest reduction percent (AAPC: -9.1; CI95%: -13.8; -4.3), followed by the Southeast region (AAPC: -8.7; -14.6; -2.5). The North and South regions showed the largest number of joinpoints in the time series. The highest incidences were recorded in the male population, however, stable (AAPC: 2.14; CI95%: -8.3; 0). In the age group analysis, the trend was decreasing for the groups from 0 to 4 years old (AAPC: -7.7; CI95%: -12.6; -2.4), 5 to 9 years old (AAPC: -7.3; CI95%: -13.6; -0,4) and 10 to 14 years old (AAPC: -5.5; CI95%: -10.3; -0.3). It was found that although Visceral Leishmaniasis is an endemic disease in Brazil, there was a decrease in its incidence rate from 2007 to 2020.


introduction
Visceral leishmaniasis (VL) or kala-azar is a zoonosis of worldwide distribution caused by protozoa of the genus Leishmania that are transmitted by sandflies 1,2 .The main urban reservoirs of VL are dogs 3 .
This disease is considered a problem of Public Health of international importance, especially affecting tropical countries, whose socio-environmental conditions favor the development and proliferation of Lutzomyia longipalpis, the main vector of Leishmania chagasi, the causative agent of VL in Latin America [2][3][4][5] .
It is a disease of wide distribution in Asia, Europe, the Middle East, Africa, and the Americas, with the highest incidence in rural and suburban areas 6,7 .
VL is the most severe form of leishmaniasis, being potentially fatal due to its multisystem involvement and the tropism of its agentS for hematopoietic organs, such as the spleen, liver, and bone marrow 3,8 , and affects more frequently socially vulnerable populations and individuals with immunosuppression conditions, such as malnourished children, patients with HIV/Aids infection, elderly people with comorbidities, among other conditions that impair the host's immune response 3,4,9 .
It is estimated that 400 thousand of new cases of this disease occur annually across the globe 1,10 .In the Americas, 13 countries are endemic, and from 2001 to 2020, 67,922 new cases were recorded, with an average of 3,400 occurrences per year.In 2020, of the total number of new cases in the American continent, 97% were reported by Brazil and the others by Argentina, Bolivia, Colombia, Paraguay, Venezuela, and Uruguay 4,11 .
In the last three decades, however, many aspects of the VL ecoepidemiology were reviewed and enabled the development of surveillance measures by the control bodies, such as the incorporation of actions and activities in the Visceral Leishmaniasis Surveillance and Control Program (VLSCP).Since 2011, the Regional Leishmaniasis Program (RLP) by the Pan American Health Organization (PAHO) 11 has been monitoring the behavior of this disease in the Americas region with planning and control measures.
The identification of territorial units of greater epidemiological importance is a factor that needs to be considered in the planning of VL promotion, prevention, surveillance, and control measures by health agencies, especially in endemic regions, as is the case of the national territory.Despite this reality, no recent study was identified in Brazil on the behavior of the disease over the years in its different regions, Federation units, and according to sociodemographic characteristics.Therefore, this study sought to analyze the trends of VL incidence in the country from 2007 to 2020 by major national regions and Federation units, and according to the gender and age group of those affected.

method
This is an ecological time series study to analyze the trends of VL incidence rates in the population of Brazil, from 2007 to 2020.
The study scenario is Brazil, the largest nation in South America in terms of land area and population.Information on new VL cases (CID 10 -B55.0) was collected from the Ministry of Health's Information System on Notifiable Diseases (SINAN Net) database, available on the website of the Department of Informatics of the Unified Health System (DATASUS; https://datasus.saude.gov.br/informacoes-de-saude-tabnet/).
The collection of data took place on March 20, 2022.SINAN Net is a system that aims to collect, transmit, and disseminate data routinely generated by the Epidemiological Surveillance System of the three levels of government in Brazil, through a computerized network, to support the investigation process and provide subsidies for the analysis of epidemiological surveillance information on compulsory notifiable diseases, as it is the case with VL 12 .
Data on the population residing in the country by gender and group age were obtained through demographic information from the Brazilian Institute of Geography and Statistics (IBGE), which is information based on censuses and the inter-census population estimates (www.ibge.gov.br/estatisticas/sociais/populacao).
VL cases were tabulated using DATASUS Tabnet and Microsoft Excel Office 2013 was used to organize the database, build indicators, and create tables.
Then, a joinpoint regression analysis model was used for the time analysis.This model verifies if one line with multiple segments is statistically better to describe the time evolution of a data set than a straight line, or with fewer segments.In this way, it allows identify the trend of the indicator (increasing, stable, or decreasing) and the points where there is a change in this trend, allowing us to know the annual percent change (APC) and that of the entire period, called average annual percent change (AAPC) 13,14 .
The incidence rates were considered a dependent variable (Y) and calendar years as an independent variable (X).For each trend detected, 95% confidence intervals (CI95%) and p values (5% significance level) were considered.Non-significant p values resulted in a stability trend (accepting the null hypothesis that the incidence rates have not changed over the years).On the other hand, significant p values resulted in a classification of growth trend (positive APC or AAPC) and decreasing trend (negative APC or AAPC) 13,14 .
All tests were performed on Joinpoint Regression Program, version 4.9.0.1, and to minimize the effect of eventual autocorrelations, the option "fit an autocorrelated errors model based on the data" available on the software was used.

Results
Between 2007 and 2020, 45,270 new cases of VL were recorded, with a predominance in the Northeast region (52.78%).The male gender was responsible for 64.13% of the occurrences.As for age, the most affected group was from 1 to 4 years old (34.33%).The year with the highest incidence of VL was 2017, with 1.98 cases/per 100 thousand inhabitants.
Concerning the analysis by federation unit (FU), the time modeling showed that five regions and the Federal District presented decreasing trend, with one from the North region, one from the Northeast, one from the Southeast, and tho from the Central-West (two states and the Federal District).On the other hand, 16 presented stationary patterns, with four in the North, seven in the Northeast, two in the Southeast, two in the South, and 1 in the Central-West; and four showed an increasing trend, one in each region (except for the Central-West region) (Table 1).
From 2007 to 2020, the autochthony of the disease was confirmed in 26 federation units, distributed in five Brazilian regions, with the Northeast region being responsible for the largest number of cases in the country (n = 23,893; 44.6%).Only the state of Acre, in the North region, did not present VL cases during the studied period.The state of Tocantins, in turn, concentrated the highest incidence of VL throughout the data series.

Discussion
In Latin America, more than 95% of VL cases occur in Brazil, most of them in the Northeast region 1,11 .This scenario reflects that VL is a relevant public health problem in the national territory and makes the country a priority area for measures to monitor and control the disease, either through epidemiological or environmental surveillance actions.In 2020, the lowest number of VL occurrences of the time series was recorded in the national territory, a phenomenon that was significantly reflected in the incidence of this disease (n = 1,933; 0.91 cases/100 thousand inhabitants).This significant decrease in the incidence of VL cases may represent an indication of the reduction in the force of morbidity and in the magnitude of the endemicity of this zoonosis nationwide, formerly treated as a disease of increasing incidence 15 .And it may also be one of the effects generated by the COVID-19 pandemic 16,17 .
In analyzing the data, it is observed that there was a formation of an inflection point (joinpoint) in the time series of the incidence rate for the national territory in 2018.This behavior was influenced by the reduction in the number of cases at the level of states and regions, especially in the Northeast, which concentrates the greatest burden of the disease in the country and which, according to the data series, presented stability in seven of its Federation Units, decrease in Ceará, and increase only in the state of Alagoas.
Two studies carried out in Ceará indicated heterogeneity of VL in that state.In the first one, VL presented a trend of increase and expansion for the Central-West and East regions between 2003-2017, and a decrease from 2016 on 18 .In the second one, which also used segmented time regression, the global incidence rate of VL showed an increasing trend in the capital between 2007-2017 and a decrease for the interval 2015-2017 19 .These diverse findings possibly result from time frames and trend analysis adopted in the studies.
Another study, which had the state of Alagoas as its analysis space, confirms a progressive evolution of VL incidence rates in the Federation Unit, showing geographic expansion, a trend of zoonosis persistence in areas that already had reported cases, and overall strengthening of the endemic status of the disease in that territory between 2007 and 2018 20 .
A historical series study of VL in the Northeast region developed by Batista et al. 21highlighted the cyclical nature of the disease.The authors identified epidemic peaks in 1983-1984, 1993-1994, 2003-2004, and 2013-2014 in Piauí and a general trend of stability for VL incidence, mortality, and lethality rates between 1971 to 2018 in the state.Another study, in agreement with our findings, also indicated a decreasing trend of VL incidence for Tocantins 22 .Some national and Latin American studies also point to this cyclical behavior and the het-  erogeneous nature of VL transmission, which has varied between high and low incidences 19,[23][24][25] .In a study developed by Servadio et al. 26 , the asymmetry of VL distribution in the country is also revealed, with emphasis on the few states that followed the same trend of national incidence.In this study, the trend for the Southeast regions and the state of São Paulo was decreasing.In agreement, a survey that evaluated the spacetime distribution of VL in the western region of that state, from 2004 to 2018, also indicated a decreasing trend in the number of cases of the disease, especially after 2010 27 .The authors of the study suggest that this phenomenon may be related to VLSCP settlement in that region 27 .
During the time series, the state of Tocantins concentrated the highest burden of the disease in the country.Reis et al. 28 point out that such behavior takes place mostly in the north and south regions of that state, being influenced by high values of annual precipitation and humidity, in addition to high levels of vegetation and night  temperature -environmental conditions favorable vector reproduction and to wild reservoirs of VL and that end up favoring the increase of the disease in this territory.
The differences between the behavior of national and federation units' incidence rates suggest that different factors can influence the risk of VL among states and regions of the country.Rocha et al. 29 , Braz et al. 20, and Ribeiro et al. 30 agree that the behavior of this zoonosis in the regions of the country is directly associated with the environmental and geographic conditions of the territory, where situations of high temperature and humidity predominate, which enable a good adaption and reproduction of the vector; and precarious socio-environmental issues such as lack of basic sanitation and water supply, poor housing conditions, accumulation of waste from the peridomicile both in an urban and rural area, the intense population of vectors and canine cases of the disease, presence of livestock close to residences and proximity of households to green areas, factors that directly interfere in the adaptation and reproduction of L. longipalpis.
It is worth noting in this area that the trends of incidence rates to remain stable, with no significant variations, in most federation units, may indicate the fragility of prevention and control measures, either due to lack of effectiveness or implementation difficulties in the VLSCP actions, or possible failures in the surveillance actions of this disease.This reality added to the high occurrence and burden of this disease still creates major challenges for health services, especially for the unified system, responsible for VL surveillance and control policies nationwide.On this topic, Werneck 31 highlights that despite the efforts and resources committed to the full functioning of VLSCP, the perception is consolidated that the actions aimed at reducing the transmission of VL have not had the desired effect of reducing the incidence of this disease.
Throughout the series analyzed, there was a higher incidence of cases among males and children under 5 years of age, with a record of stability for the occurrence in males and decreasing trend of cases in females and also in the group under 5 years of age.The specialized literature mentions that the greater the number of cases in a region, the greater the vulnerability of infected children, and when affecting the group of male adults or elderly 6,10,30 .
In time, it is pertinent to consider that this work has all the limitations inherent to the fact that it is an ecological study, namely: the possibility of ecological fallacy, chance correlations, and difficulties in controlling confounding factors.It also has limitations arising from the use of secondary data, which, as is known, are subject to underreporting, eventual errors due to incompleteness, precision or inconsistency, or even underdiagnosis, a common phenomenon across the country 1 .
Finally, it is important to have in mind that the data presented here, especially those concerning the last two years of the time series, may represent one of the indirect consequences generated by the COVID-19 pandemic 16,17 .Therefore, the number of cases and consequently, the VL incidence rate in the series analyzed may be higher than what was observed, wither because of the recognized impact of the SARS-CoV-2 public health emergency in the fight against neglected tropical diseases, including the VL, or throughout the series, due to deficiencies in health services, especially in locations where assistance and surveillance actions have operational problems linked to the chronic lack of inputs and financial, material, or personnel resources.It should be noted, however, that the results of this study were based on official sources of information, the same ones adopted for decision-making regarding public policies to combat and monitor VL nationwide.

Conclusion
Despite VL being an endemic disease in the national territory, there was a statistically significant decrease in the general incidence rate of this anthropozoonosis in Brazil for the period studied.It is important to consider, however, that this disease remains an important public health problem in the country and its regions, because, despite the verified trends of reduction in the general rate for the State, it is concomitantly observed inequalities in the epidemiological behavior of this indicator at the level of the political-administrative units, with an important portion of Federation units with incidence rates that remain on an increasing trend or in a stationary behavior.In this way, this study reaffirms the need to enhance effective measures to promote VL control in the country, with emphasis on the territories with the highest burden of this disease.

Collaborations
CJ Santos Júnior , KC Lima, MM Santos: conception and design of the study, analysis and interpretation of data, writing -original draft, final approval of the version to be submitted; KC Lima, MM Santos: project administration, writing -review e editing, final approval of the version to be submitted; FCCO Lins, JP Silva: funding acquisition, analysis and interpretation of data, final approval of the version to be submitted.funding Laboratório de Inovação Tecnológica em Saúde.

Table 1 .
Percentage of annual average variation (AAPC) and percentage of annual variation (APC) of VL incidence rates in the regions and Federation units in Brazil (2007-2020).

Table 1 .
Percentage of annual average variation (AAPC) and percentage of annual variation (APC) of VL incidence rates in the regions and Federation units in Brazil (2007-2020).

Table 2 .
Percentage of annual average variation (AAPC) and percentage of annual variation (APC) of VL incidence rates in Brazil by socio-demographic variables (2007-2020).