Spatio-temporal dynamics of visceral leishmaniasis transmission in a highly endemic region of Brazil

visceral leishmaniasis cases occurred in Americas, and Maranhão is the Brazilian state with the highest number of registered cases. Aim: to analyze the spatio-temporal dynamics of visceral leishmaniasis transmission in a Brazilian region with high endemicity between 2009 to 2017. Outlining: We carried out an ecological and time series study using spatio-temporal analysis techniques. A time-trend analysis was performed by the segmented linear regression. High-risk clusters were identified through spatial autocorrelation (Moran’s global and local indexes) and space-time scan statistics. Results : There were 5,128 visceral leishmaniasis cases, and it was observed increasing trends of new cases in the general population, among men, adults ≥20 years old, especially ≥60 years old. VL-HIV coinfection, mortality and lethality were crescent. Spatial analysis revealed intense visceral leishmaniasis transmission in almost the entire state and high-risk priority areas. Implications : Visceral leishmaniasis is in a substantial geographical expansion, demonstrating that the surveillance policies need to be reformulated.


INTRODUCTION
] In both Americas, VL is caused by Leishmania infantum protozoan, whose urban reservoir is the domestic dog. 3 The transmission happens when the female sandfly (Lutzomiya longipalpis) bites the host.This vector is very well adapted to urban sites with high populational density. 4 is estimated that 1 billion people live in VL endemic regions worldwide and that 50,000 to 90,000 news cases happen per year.In the Americas, the disease is endemic in 12 countries, including Brazil, 5 which is responsible for 97% of the registered cases in 2018. 6] The vector is disseminated throughout the country and has become adapted to inhabit the modified environment by anthropic actions. 9n the 90s, about 90% of notified cases were from the Northeast of Brazil, but with the VL dissemination to other regions, in 2012, the Northeast represented only 43.1% of national cases. 10wever, 56% of VL deaths, between 2000 to 2011, occurred in this region.
Maranhão, located in the Northeast region, is the state with the highest number of VL cases.The endemic scenario stems from the conducive environment to disease transmission, due to unplanned environmental destruction, industrialization, and urbanization, lack of sanitation and poor housing conditions.[13] It is notable that these socio-environmental conditions make Maranhão conducive to the development of several tropical diseases, whose vectors are mosquitoes, such as VL, 13 which has been associated to poverty and poor living conditions. 14us, the aim of this study is to analyze the spatio-temporal dynamics of VL transmission in Maranhão, a Brazilian region with high endemicity.
We hypothesize that the spatial distribution of VL in the state of Maranhão is not random (principle of spatial independence) but presents a pattern of clustering due to proximity to municipalities with high rates of the disease.

Study Design
An ecological and time series study that used Spatio-temporal analysis techniques, including all VL confirmed cases from Maranhão, Northeast of Brazil, during 2009-2017.The units of analysis were the 217 municipalities of the state.

Study area
The state of Maranhão is located in the Northeast region of Brazil (4°57'39.4"S45°16'27.9"W),which possesses a territorial extension of 329,642.170km² and estimated population of 6,574,789 inhabitants, its municipalities are grouped in 5 mesoregions (North, South, East, West, and Center). 15

Variables and Measures
Incidence rates (per 100,000 inhabitants) were considered main variables of the study.inhabitants, in 2017, with an annual increment of 6.8 (CI95%: 1.5 to 12.4).There was a rising trend of new cases in the general population (APC: 6.1; CI95%: 0.6 to 12.0), as well as among males and age groups ≥ 20 years old, especially elderly (APC: 24.2; CI95%: 13.5 to 35.9).In addition, VL-HIV coinfection (APC: 8.9; CI 95%: 1.9 to 16.4), mortality rate (APC: 17.1; CI95%: 9.1 to 25.6) and lethality (APC: 5.5; CI95%: 3.2 to 7.8) in general population evidenced significant increasing trends.VL is in expansion and widely spread throughout the state, since there was a significant increment in the proportion of municipalities with VL transmission (APC: 5.5; CI95%: 3.2 to 7.8).The spatial analysis presented in Figure 1 corroborates with this finding.The maps with spatial distribution of triennial crude incidence rates (Figure 1A) and smoothed (Figure 1B   Five spatio-temporal high-risk clusters were identified through space-time scan statistics (Table 3), which can be visualized in

DISCUSSION
The results revealed that VL is a serious public health issue in expansion in the state of Maranhão, once the state remains leading the number of VL registered cases in regional and national levels.The spatio-temporal analysis evidenced increasing trends in VL incidence and intense transmission in all mesoregions, with incidence rates higher than the national rate registered in 2017 (1.98 cases/100,000 inhabitants). 22e highest VL prevalence occurred among males, < 5 years old, nonwhite skin color, urban residents and low education.[26][27][28] Despite the occurrence of most cases being among children and adolescents, there were rising trends among adults, especially among elderlies.
Young children are more susceptible to VL infection due to immaturity of an immune response, which can be aggravated by malnutrition, a common phenomenon of endemic areas. 3,29owever, in a study performed in Rio Grande do Norte, Brazil, similar findings were observed, since it was noticed a progressive increase of VL among adults, 30 possibly associated with the aging population and decrease of fecundity in the country. 15L can have more severe consequences at the extremes of age, particularly in the elderly, due to the burden of comorbidities and immunosenescence. 31rtality, lethality, and VL-HIV co-infection increased significantly in the study period.Among the main contributive factors to the rise of lethality is the age < 5 years old, 32 late diagnosis, mainly in elderly people, 33 and the expansion of the epidemic in individuals with comorbidities, 34 such as VL-HIV coinfection.1 HIV-positive patients are more susceptible to develop VL, which is considered an opportunistic infection that accelerates the HIV replication and the progression to AIDS. 35e  38 The phenomenon of migration enables both the introduction of the etiologic agent and the insertion of susceptible individuals in endemic areas with poor living conditions and no proper infrastructure and sewage.
Additionally, it is important to mention the adaptation ability of vector, L. longipalpis, to indoor environment, which can be found practically throughout the state. 24,38e Moran maps pointed out to the West, Center and East mesoregions, that showed higher concentration of cases and significant spatial dependence.On the other hand, the primary high-risk spatio-temporal cluster comprised municipalities from West and Center mesoregions, which had the worst HDI of the state 39 and are located into the Brazilian Legal Amazon.Similarly, spatio-temporal clustering of leprosy cases at the same region was observed. 40his finding is concerning because the overlapping of several infectious diseases could overwhelm the health surveillance system.
The Brazilian Legal Amazon is a strategic region for great development projects, the agribusiness, and extensive livestock.Granting the advances in the regional economy, nonetheless there were serious changes in the ecosystem, caused by deforestation, as well as due to the implementation of industrial projects that favored populational growth, as in the cities of Açailância and Imperatriz, 13 making the scenario of social vulnerability more critical. 41vironmental modifications, massive human migrations, unplanned urbanization, deforestation, and irregular occupation of forest areas, combined with low quality sewage and low host immunity are related to the occurrence of VL new cases. 3xcepting some forest protection and indigenous areas, part of the coast and far South of the state of Maranhão has already undergone important anthropic modification. 42onsequently, these preserved areas were those that exhibited a lower risk for VL transmission.Accordingly, one of the priorities of the development policies should be the promotion of the socio-environmental sustainability of Maranhão. 42 is fundamental to know the spatial, temporal, and spatio-temporal patterns of the diseases to effective surveillance, mainly in those vector-borne diseases like VL. Spatio-temporal analysis techniques have been showing to be useful for the comprehension of the occurrence of health events in the territory. 43owever, their applicability in nationwide surveillance and disease control services are still incipient.
This study has some limitations, particularly related to underreporting and the quality of records in northeastern municipalities.This may be due to the operational difficulties of surveillance services and the fragility of the primary care network in the most underserved and hard-to-reach municipalities.

Sources
Morbidity data, clinical and demographic characteristics of registered cases were obtained from Information System for Notifiable Diseases (Sistema de Informação de Agravos de Notificação -SINAN) database of the Secretariat of Health Surveillance of the Brazilian Ministry of Health (Secretaria de Vigilância em Saúde do Ministério da Saúde -SVS/MS).Population estimations and the digital cartographic mesh (shapefile extension) of the Universal Transverse Mercator (UTM) system -Terra Datum horizontal model (SIRGAS 2000), segmented by municipalities and mesoregions were obtained from databases of the Brazilian Institute of Geography and Statistics (Instituto Brasileiro de Geografia e Estatística -IBGE).
) point intense transmission in all mesoregions of the state.Among 2009-2011, VL new cases concentrated in the East, Center, and South of Maranhão.From 2012 to 2014, an increase in transmission intensity was observed in areas that had sporadic transmission previously.In the last triennium (2015-2017), the VL transmission in all mesoregions and the rise of the transmission intensity is remarkable, mainly in the Midwest of the state.

Figure 1 .
Figure 1.Spatial dynamics of VL transmission in municipalities of Maranhão, Brazil, grouped into mesoregions and represented by triennial incidence rates (per 100,000 inhabitants)

Figure 2 .
Figure 2. Spatial and spatiotemporal analysis for VL transmission in municipalities of Maranhão, grouped into mesoregions and represented by average incidence rates (per 100,000 inhabitants) of entire period (2009-2017) Figure 2D.The cluster no. 1 represents the primary cluster, and the others are secondary clusters.The primary cluster occurred during 2011-2014, with the highest number of VL cases in the state and was limited to the Center and West of Maranhão.The cluster no. 2 (2016-2017) comprised the highest number of municipalities.Nevertheless, the cluster no. 3 (2013-2015) had the highest relative risk (RR: 3.64).It shows that, despite the decrease of risk of the exposed population in developing VL between 2015 to 2017, the number of municipalities with VL transmission increased.

Furthermore, it is
not possible to establish casual link between individual variables and the occurrence of VL.Despite these limitations, our results represent the epidemiological scenario of LV in the Maranhão state over a 9-year period and demonstrate the usefulness of spatiotemporal analyses for the surveillance and control of public health diseases.These analyses allow for the identification of high-risk priority areas for transmission and provide an understanding of the association between disease dynamics and social phenomena occurring in the region.These interventions need to be improved through a more coherent health policy with local reality, whose implementation is supported by a focused research agenda.

20 Spatio-temporal cluster analysis
table and map.Relative risks (RR) to VL occurrence in each cluster were calculated.The results were statistically significant when p-value < 0.05, using 999 Monte Carlo simulations. 21periodicos.ufpi.brRev Pre Infec e Saúde.2024;10:5747 Softwares Microsoft Office Excel 2016 (Microsoft Corporation; Redmond, WA, EUA), TerraView 4.2.2 (Nacional Institute for Spacial Research, INPE, SP, BR), QGIS 2.18.10 (Open Source Geospatial BR), QGIS 2.18.10 (Open Source Geospatial Foundation), JointPoint Regression 4.3.1.0(US National Cancer Institute, Bethesda, MD, EUA) and SaTScan 9.1.1(Harvard Medical School, Boston and Information Management Service Inc., SiVLer Spring, MD, EUA) were used to analysis and data processing.Ethical Considerations The present study used aggregated secondary data available in public domain and followed the Brazilian National Health Council's (Conselho Nacional de Saúde do Brasil) and Declaration of Helsinki's recommendations.All analyzed and presented data were anonymous, dispensing the necessity of the Free and Informed Consent Form.This research project was approved by the local Ethics Committee (Comitê de Ética em Pesquisa da Universidade Federal de Sergipe), registered under the number: 2.537.671.RESULTS According to the research, 5,128 VL cases were confirmed in the state of Maranhão during 2009-2017, with an average annual prevalence rate of 8.4 cases/100,000 inhabitants in the general population.Most cases were new (4,735/92.3%)with average annual incidence corresponding to 7.76 cases/100,000 inhabitants.Table 1 shows the baseline characteristics of the study population.VL affected predominantly males (63.8%), < 5 years (47.5%),nonwhite people (89%), urban residents (68.5%), low education people (26.3%) and that were later cured (56.7%).Lethality was 8.1% and the percentage of VL-HIV co-infection was 8.6%.It is important to highlight that there was no outcome register in almost 20% of the cases.

Table 3 .
Spatiotemporal clusters of VL new cases (per 100,000 inhabitants),Maranhão, Brazil, 2009-2017 Several factors may have contributed to VL dissemination, started in the 2000s, among them, the intense migratory flow between municipalities and states, especially next to Teresina, Piauí, and in neighboring of Vale do Rio Doce railroad, as well as in cities with intense deforestation.