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Aims: This study describes the spatio-temporal dynamics of new visceral leishmaniasis (VL) cases notified in Brazil between 2001 and 2020., Methods and Results: Data on the occurrence of the disease were obtained by means of the Notifiable Diseases Information System of the Brazilian Ministry of Health. Joinpoint, temporal generalized additive models and conditional autoregressive (CAR) models were used to analyse the temporal evolution of the rates in Brazil, states and regions. Spatio-temporal generalized additive and CAR models were used to identify the distribution of annual risks of VL occurrence in the Brazilian territory in relation to variation in the spatial average. There were 63,966 VL cases in the target period (3.198 cases/year), corresponding to a mean incidence rate of 1.68 cases/100,000 inhabitants. Of these, 4451 resulted in deaths, which gives a mean mortality rate of 0.12 deaths/100,000 inhabitants and a case fatality of 6.96%. The highest incidence rate was found in the North region, followed closely by the Northeast region, which presented the second and first highest mortality rates, respectively. For all of Brazil, and in the Northeast region, there were stability in the incidence rates, while the other regions showed an increasing trend in different time segments in the period: Central-West up to 2011, North up to 2008, Southeast up to 2004, and South up to 2010. On the other hand, all regions experienced a reduction in incidence rate during the last years of the series. The Northeast region had the highest number of municipalities with statistically significant elevated relative risks. The spatio-temporal analysis showed the highest risk area predominantly in the Northeast region in the beginning of the time series. From 2002 to 2018, this area expanded to the interior of the country., Conclusions: The present study has shown that VL has expanded in Brazil. However, the North and Northeast regions continue to have the highest incidence, and the risk of infection has decreased in recent years., (© 2023 Wiley-VCH GmbH. Published by John Wiley & Sons Ltd.)

Background: Leishmania RNA virus 1 (LRV1) is commonly found in South American Leishmania parasites belonging to the subgenus Viannia, whereas Leishmania RNA virus 2 (LRV2) was previously thought to be restricted to the Old-World pathogens of the subgenus Leishmania., Objectives: In this study, we investigated the presence of LRV2 in strains of Leishmania (L.) infantum, the causative agent of visceral leishmaniasis (VL), originating from different hosts, clinical forms, and geographical regions., Methods: A total of seventy-one isolates were screened for LRV2 using semi-nested reverse transcription-polymerase chain reaction (RT-PCR) targeting the RNA-dependent RNA polymerase (RdRp) gene., Findings: We detected LRV2 in two L. infantum isolates (CUR268 and HP-EMO) from canine and human cases, respectively., Main Conclusions: To the best of our knowledge, this is the first detection of LRV2 in the New World.

Visceral leishmaniasis (VL) is a pressing public health problem in Brazil. The proper implementation of disease control programs in priority areas is a challenge for healthcare managers. The present study aimed to analyze the spatio-temporal distribution and identify high risk areas of VL occurrence in the Brazilian territory. We analyzed data regarding new cases with confirmed diagnosis of VL in Brazilian municipalities, from 2001 to 2020, extracted from the Brazilian Information System for Notifiable Diseases. The Local Index of Spatial Autocorrelation (LISA) was used to identify contiguous areas with high incidence rates in different periods of the temporal series. Clusters of high spatio-temporal relative risks were identified using the scan statistics. The accumulated incidence rate in the analyzed period was 33.53 cases per 100,000 inhabitants. The number of municipalities that reported cases showed an upward trend from 2001 onward, although there was a decrease in 2019 and 2020. According to LISA, the number of municipalities considered a priority increased in Brazil and in most states. Priority municipalities were predominantly concentrated in the states of Tocantins, Maranhão, Piauí, and Mato Grosso do Sul, in addition to more specific areas of Pará, Ceará, Piauí, Alagoas, Pernambuco, Bahia, São Paulo, Minas Gerais, and Roraima. The spatio-temporal clusters of high-risk areas varied throughout the time series and were relatively higher in the North and Northeast regions. Recent high-risk areas were found in Roraima and municipalities in northeastern states. VL expanded territorially in Brazil in the 21st century. However, there is still a considerable spatial concentration of cases. The areas identified in the present study should be prioritized for disease control actions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Leishmaniasis represents a major neglected public health problem and the control measures have not been successful in Brazil. Recent studies have shown leishmaniasis importance to Brazilian border zones which reinforces the need to investigate its spread in those regions. This study aimed to analyze epidemiologic profile and its spatial distribution or aggregation process in both tegumentary and visceral leishmaniasis in the Brazilian border strip from 2009 to 2017. This is an ecological study of the epidemiological profile and spatial patterns encompassing municipalities in the Brazilian border strip. The presence of spatial autocorrelation and determination of priority areas for disease control were performed using global (Moran I) and local (LISA) Moran spatial techniques. The annual mean coefficients of tegumentary and visceral leishmaniasis were 29.8 and 0.6 by 100,000 inhabitants in the border strip, respectively. The indigenous population rates of leishmaniasis in the border zone appears to be higher than in the rest of the country (cutaneous changed from 33.2% to 6.6% and visceral rising from 1.0% to 17.5%) in the period. The most affected municipalities were located in the North and Central arches of the border zone. The results can subsidize the development of more targeted and effective strategies that can contribute to the surveillance and control of leishmaniasis in border zones, as the provision of epidemiological and spatial data on the disease. For better control of the disease, we recommend and emphasize the need to integrate public health policies of neighboring countries., Competing Interests: Declaration of Competing Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in the paper “Spatio-temporal patterns and integrated approach to prioritize areas for surveillance and control of visceral leishmaniasis in a large urban agglomeration in Brazil”., (Copyright © 2022. Published by Elsevier B.V.)

There are gaps in the knowledge of the factors associated with canine visceral leishmaniasis (CVL). Moreover, there is a need for studies conducted with appropriate sample selection and with standardized diagnostic methods, to assess the current infection status of animals. This study analyzed factors associated with Leishmania infantum infection in dogs from urban areas endemic for CVL in Brazil. Data from four cities in different regions of the country (Fortaleza, Brasília, Palmas, and Bauru) were included, encompassing a large and heterogeneous sample group. Dogs were considered infected if they had positive results in parasitological tests (skin lesion culture, histological or immunohistochemical analysis of skin). Data analysis consisted of logistic regression with adjustment for the effect of cities as cluster variables, using generalized estimating equations. The canine positivity for L. infantum was 9.8%. Bauru had the highest percentage (18.7%), followed by Brasília (8.4%), Fortaleza (7.9%), and Palmas (4%). Male animals were twice as likely to be infected as females (Confidence Interval (CI): 1.5-2.8). Dogs living outdoors were 1.5 times more likely to be positive (CI: 1.4-1.6). Dogs living in households rearing chickens were 40% less likely to be infected (CI: 0.5-0.8). A significant multiplicative interaction indicated that a protective association between purebred and CVL was stronger among dogs older than seven years. These findings provide evidence for the role of individual and environmental factors on L. infantum infection in dogs from endemic urban areas. They may be used for identifying groups of animals at higher risk for delivering control interventions., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Responsible companion animal guardianship (RCAG) comprises a set of concepts involving activities, behavior and care that guardians must provide to ensure the welfare of their animals. When such principles are disregarded, the risk of animals developing zoonotic diseases, such as canine visceral leishmaniasis (CVL), increases. This disease is a public health problem in many urban settings in Brazil because dogs are the main reservoirs of Leishmania and are involved in the transmission of the parasites to humans. Our analytical cross-sectional epidemiological survey aimed to investigate the prevalence of CVL in a city in southeastern Brazil and to establish the association between the disease and a number of predictor variables including dog traits, socioeconomic status of guardians, ecological features of the domicile and RCAG., Results: Our study showed that the global prevalence of CVL in the sample canine population was 6.7% (47/704). All variables related to better dog care were associated with lower chances of infection. Multiple regression analysis revealed that the chances of animals being seropositive for CVL were significantly (p < 0.05) higher when guardians had no formal education or possessed a university degree (vs. those with complete primary or secondary schooling) and when dogs were sheltered outside the house and had free access to the streets. An additional novel finding was that dogs that were acquired as puppies presented half of the chance of developing the disease in comparison with those acquired at the adult stage. Geographically weighted logistic regression coefficients showed that the strengths of the predictor/CVL associations varied depending on the studied geographical space. Both models demonstrated that the associations were always in the same directions., Conclusions: Our findings indicate that regardless of age and mode of acquisition, adult dogs should be submitted to clinical evaluation and tests for CVL. RCAG can exert positive effects on the control of CVL., (© 2022. The Author(s).)

The failures in the treatment of leishmaniasis is an increasing problem around the world, especially related to resistance. Thus, we describe the synthesis and in vivo anti-Leishmania activity of alkylphosphocholine and alkyltriazoles; besides, their likely action mechanisms stem from some eventual inhibition of parasite enzymes using computational tools. These compounds were tested in an in vivo hamster model infected with Leishmania Leishmania infantum chagasi. Fifty days after parasite inoculation, the two compounds 12-azidedodecylphosphocholine (3) and 3-(1-(12-fluorododecyl)-1H-1,2,3-triazol-1-yl)propano-1-ol (9), were separately administered once a day as oral suspensions (25 and 12.5 mg/kg/day, respectively) during ten days, and their efficacy was compared to the reference compound pentavalent antimonial Glucantime (GLU). Compound 3 significantly reduced the number of parasites in the spleen (4.93 × 10 2 amastigotes/g) and liver (4.52 × 10 3 amastigotes/g). Compound 9 reduced the number of amastigotes in the spleen to 1.30 × 10 4 and 1.36 × 10 3 amastigotes/g in the liver. GLU was the most effective overall treatment (7.50 × 10 1 and 2.28 × 10 2 amastigotes/g in the spleen and liver, respectively). The high activity levels of these compounds in vivo may stem from their high in vitro leishmanicidal activity and lipophilicity. The in silico absorption, distribution, metabolism, and excretion studies also showed some anti-Leishmania potential. Compound 9 had more lipophilic characteristics than those of compound 3. In silico studies of the nine enzymes of compounds 3 and 9 showed significant evidence of interactions with nicotimidase and tyrosine aminotransferase, demonstrating possible inhibition enzymes present in L. (L.) infantum chagasi. These compounds could be a promising template for developing a new class of leishmanicidal agents, by oral route, and deserve further investigation to explore different therapeutic regimens., (Copyright © 2021. Published by Elsevier Inc.)

Dogs have different susceptibility degrees to leishmaniasis; however, genetic research on this theme is scarce, manly on visceral form. The aims of this systematic review were to describe and discuss the existing scientific findings on genetic susceptibility to canine leishmaniasis, as well as to show the gaps of the existing knowledge. Twelve articles were selected, including breed immunological studies, genome wide associations or other gene polymorphism or gene sequencing studies, and transcription approaches. As main results of literature, there was a suggestion of genetic clinical resistance background for Ibizan Hound dogs, and alleles associated with protection or susceptibility to visceral leishmaniasis in Boxer dogs. Genetic markers can explain phenotypic variance in both pro- and anti-inflammatory cytokines and in cellular immune responses, including antigen presentation. Many gene segments are involved in canine visceral leishmaniasis phenotype, with Natural Resistance Associated Macrophage Protein 1 (NRAMP1) as the most studied. This was related to both protection and susceptibility. In comparison with murine and human genetic approaches, lack of knowledge in dogs is notorious, with many possibilities for new studies, revealing a wide field to be assessed on canine leishmaniasis susceptibility research., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Human and canine visceral leishmaniasis (HVL and CVL, respectively) represent serious public health issues in Brazil. The surveillance and control measures currently employed have had limited effect in impeding the territorial expansion of the disease and in reducing the number of cases. We have investigated the space-time distribution of HVL incidence rates and CVL prevalence in the coverage areas of the 148 primary healthcare units in Belo Horizonte (MG, Brazil) during a 6-year period in order to identify those that should be prioritized for disease control actions. Data were smoothed using the empirical Bayes method and analyzed by space-time scanning and application of univariate global Moran's I index and local indicators of spatial association (LISA) statistics to identify spatial autocorrelations. Point data of CVL were analyzed using the Kernel method. Bivariate global Moran's I and LISA techniques were employed to identify spatial correlations between HVL and CVL. Based on our results, we were able to formulate two proposals for establishing the prioritization of coverage areas, namely: (i) classification of maximum priority areas as identified by bivariate LISA for HVL and CVL, and (ii) combination of maximum priority areas with high priority areas as identified by univariate LISA for HVL. According to our proposals, 27 coverage areas in Belo Horizonte were categorized as maximum priority and a further 13 were classified as high priority. Our proposals, which are based on practical, feasible and inexpensive statistical tools, will contribute to a better understanding of VL distribution in urban settings and improving the efficiency of governmental control programs., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Visceral Leishmaniasis is a chronic and lethal, parasitic disease. In the later infection stages, it is known that expressive hematological disorders can be observed, including changes in the frequency and phenotype of certain leukocytes. There is a lack of good prognostic indicators to characterize the on-goin clinical status of the patient. In this study, we have analyzed the frequency of monocyte subpopulations in mice infected with Leishmania major (L. major). Our results show a significant correlation between increased blood monocyte frequency and lesion development in both BALB/c and in the C57BL/6 mice infected with L. major. In BALB/c mice we observed a significant correlation between the frequency of GR1 + monocytes and lesion size. Furthermore, treatment of infected BALB/c mice with Anfotericin B, to resolve lesions, resulted in a lower frequency of GR1 + monocytes compared to untreated infected BALB/c mice. C57BL/6 infected mice, which normally resolve infections, show decreased numbers of monocytes during the healing phase of infection. The results indicate that disease severity can be predicted by analyzing monocyte frequency. Thus, we propose that the frequency of monocytes, can be used to define the severity of the disease as well as the success of the treatment in experimental leishmaniasis., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Canine visceral leishmaniosis (CVL), a parasitic disease caused by Leishmania infantum, may evolve to a chronic condition and lead to death. Evaluation of infected dogs is important to establish the clinical and laboratory parameters involved in the evolution of the disease. The objectives of the present study were to discriminate a canine population (n = 52) into sub-clinical and clinically affected dogs based on signs and scores, to evaluate the hematological, biochemical, histopathological and parasitological parameters of the two dog groups, and to analyze the results by multivariate regression analysis with the aim of establishing biomarkers of CVL clinical disease. The most common signs observed in the clinically affected dogs (n = 29) were hyperkeratosis, weight loss, onychogryphosis, pale mucosa and lymphadenomegaly. In the multivariate analysis, animals presenting high IgG avidity index and low red blood, lymphocyte and eosinophil counts, and low serum urea concentration had an increased probability of being classified as clinically affected (p <  0.05). All five parameters were considered to be strong biomarkers for monitoring the clinical disease, while IgG avidity percentage was strongly correlated with the number of clinical signs and could function as an indicator of the duration of infection. This is the first report on the application of IgG avidity and of multivariate regression analysis in establishing associations between the clinical signs of CVL and host biomarkers. Since avidity index (AI) percentages were strongly correlated with the number of clinical signs, it could be useful in clinical practice for auxiliary diagnosis of CVL and monitoring disease progression. A limitation of this study is the lack of information on co-infections by Anaplasma platys, Babesia canis vogeli, Ehrlichia canis and Hepatozoon canis. Therefore future studies should evaluate the influence of such co-infections on the associations studied using multivariate methods with larger samples., (Copyright © 2018 Elsevier B.V. All rights reserved.)

One of the key components of the Brazilian Program for the Control of Visceral Leishmaniasis (PCLV) is the euthanasia of Leishmania-infected canine reservoirs, the detection of which depends on a screening procedure involving a Dual Path Platform ® (DPP) immunoassay and a confirmatory enzyme-linked immunosorbent assay (ELISA). The aims of the present study were to evaluate the reliability of these techniques in a region of recent transmission of canine VL, to follow up the seroconversion 3-4 months after the initial diagnosis of DPP reactive but ELISA indeterminate or non-reactive dogs, and to identify the species of Leishmania in circulation in the area. Each animal was submitted to DPP under field conditions, performed by municipal health workers using peripheral blood (DPP-field), to DPP under laboratory conditions using serum (DPP-lab) and to ELISA using serum. The agreements between the tests were determined using McNemar's χ 2 test, Cohen's kappa coefficient (k) at the 95% confidence interval and prevalence-adjusted bias-adjusted kappa (PABAK). Of the 1130 dogs examined, 74.2% were non-reactive in all three tests applied. Based on the PCLV positive-infection criterion, seroprevalence was 8.9% (101/1130) with 83.2% (84/101) of infected animals showing reactivity in all three tests while 7.8% (8/101) were reactive in DPP-field and ELISA and 8.9% (9/101) in DPP-lab and ELISA. The proportions of disagreements were substantial in all comparisons. Inter-rater reliability between DPP-field and ELISA (k=0.55; PABAK=0.78) and DPP-lab and ELISA (k=0.59; PABAK=0.81) were considered moderate, while that between DPP-field and DPP-lab (k=0.61; PABAK=0.79) was classified as marginally good. The proportion of seroconversions in DPP reactive animals that were initially ELISA indeterminate was significantly higher than in those that were DPP reactive but initially ELISA non-reactive. Restriction fragment length polymorphism analysis revealed the presence of Leishmania infantum, the etiologic agent of VL, in bone marrow samples from VL-infected animals. Our data showed that the techniques and protocols currently employed in the PCLV screening approach are not entirely reliable. Further consideration should be given to monitoring dogs with undetermined results in ELISA and a better training should be provided for health workers responsible for performing DPP tests applied under field conditions., (Copyright © 2017 Elsevier B.V. All rights reserved.)

In South America, visceral leishmaniasis is a zoonotic disease with severe evolution characteristics in humans, and dogs are its main reservoir. In this context, this study aimed to evaluate the clinical status of dogs from a Brazilian endemic area naturally, at Barra Mansa municipality, infected with Leishmania infantum, in conjunction with their histopathological profile and, in order to determine possible markers of susceptibility or resistance to the disease, parasitic DNA load, cytokine and iNOS mRNA expression profiles were investigated in lymph nodes. High levels of IFN-ɣ and IL-6 mRNA were detected. Both IFN-ɣ and IL-6 mRNA were associated with disorganization of the corticomedullary region. IFN-ɣ and TNF-α mRNA were associated with the absence of follicular hyperplasia. The regulatory pathway was remarkable with IL-10 mRNA detection and its significant association with the severity of the disease. Plasmacytosis and sinus histiocytosis were associated with high loads of parasitic DNA, but there was no significant association between the parasite DNA load and animal clinical alterations. Since high parasitic loads were found in animals with or without symptoms, clinical examination cannot be considered as a criterion for disease susceptibility assessment., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: The physical characteristics of the environment influence the composition, distribution and behavior of the vectors and mammalian hosts involved in the transmission of visceral leishmaniasis (VL), thereby affecting the epidemiology of the disease. In Brazil, urbanization of human VL is a recent phenomenon and represents an issue of particular concern to local health authorities. The present study aimed to establish the degree of spatial dependency between canine and human VL in the municipality of Divinópolis, Minas Gerais, Brazil, and to identify priority risk areas in which stricter control measures should be implemented., Methods: The selected canine population comprised 3,652 dogs distributed within 11 strata and 1,247 urban blocks. Serum samples were collected between March 2013 and February 2014. Serodiagnosis of dogs was performed using the enzyme-linked immunosorbent assay and the indirect fluorescent-antibody test. The blocks sampled for canine VL and the addresses of the 16 confirmed cases of human VL notified in Divinópolis during the period 2007-2013 were georeferenced. Spatial analysis of the data was performed using Kernel density estimation, Ripley's bivariate K-function and directional distribution methods., Results: The overall prevalence of seropositive animals was 4.63% (range 3.95-5.31) (n =169) and varied in different strata between 0.9 (range 0.0-1.91) and 8.73% (range 5.65-11.81). A positive spatial dependency was detected between human and canine VL in which the occurrence of human cases of the disease tended to concentrate in locations that were close to areas with a higher incidence of canine VL. The priority risk area could be clearly distinguished from Kernel density estimation and standard deviational ellipse plots in which the human VL ellipse was totally enclosed within the canine VL ellipse., Conclusions: The results presented herein will enable the Municipal Health Office of Divinópolis to devise a more effective management plan for human VL in which specific strategies would be applied to areas presenting different levels of risk. This spatial evaluation of leishmaniasis model could be applied in other urban areas of Brazil.

Background: In the current context of high fatality rates associated with American visceral leishmaniasis (VL), the appropriate use of prognostic factors to identify patients at higher risk of unfavorable outcomes represents a potential tool for clinical practice. This systematic review brings together information reported in studies conducted in Latin America, on the potential predictors of adverse prognosis (continued evolution of the initial clinical conditions of the patient despite the implementation of treatment, independent of the occurrence of death) and death from VL. The limitations of the existing knowledge, the advances achieved and the approaches to be used in future research are presented., Methods/principal Findings: The full texts of 14 studies conforming to the inclusion criteria were analyzed and their methodological quality examined by means of a tool developed in the light of current research tools. Information regarding prognostic variables was synthesized using meta-analysis. Variables were grouped according to the strength of evidence considering summary measures, patterns and heterogeneity of effect-sizes, and the results of multivariate analyses. The strongest predictors identified in this review were jaundice, thrombocytopenia, hemorrhage, HIV coinfection, diarrhea, age <5 and age >40-50 years, severe neutropenia, dyspnoea and bacterial infections. Edema and low hemoglobin concentration were also associated with unfavorable outcomes. The main limitation identified was the absence of validation procedures for the few prognostic models developed so far., Conclusions/significance: Integration of the results from different investigations conducted over the last 10 years enabled the identification of consistent prognostic variables that could be useful in recognizing and handling VL patients at higher risk of unfavorable outcomes. The development of externally validated prognostic models must be prioritized in future investigations.

Spatial analysis of epidemiological data may be used to assist in the implementation of surveillance and control measures against visceral leishmaniasis (VL) in endemic areas. This ecological study aimed to identify priority areas for surveillance and control of VL in São Luís, the capital of the state of Maranhão in northeast Brazil, a highly endemic area for the disease. We evaluated the spatial structure of the incidence rates of human VL and of the mean number of human and canine cases occurring between 2005 and 2007 in 355 neighborhoods (aggregated into 203 geographical analytical units) within the municipality. The presence of spatial autocorrelation was explored using global and local Moran's I statistics. A local indicator of spatial autocorrelation was used to generate maps for the identification of VL clusters. The global Moran's I index revealed a weak, but statistically significant spatial autocorrelation for human VL incidence rates (I=0.138). A total of 43 geographical analytical units, encompassing 121 neighborhoods, were identified as priority areas for implementing surveillance and control actions. For the purpose of defining an action plan for the delivery of these measures, those 16 geographical analytical units (encompassing 54 neighborhoods) identified as clusters with high incidence rates of human VL should receive the highest priority. An additional nine geographical analytical units (comprising 28 neighborhoods) showed non-significant clustering of high rates of human, and might be considered as the next priority for VL management. Finally, a further 18 geographical analytical units (covering 39 neighborhoods) had records of coexisting human and canine VL cases during the study period, and these should receive priority attention when resources become available. Spatial data analysis is a valuable tool for defining priority areas for VL surveillance in high transmission areas contributing to a more effective management of financial and technical resources, increasing the sustainability and efficiency of control efforts., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Identification of factors associated with Leishmania infection in dogs is essential for targeting visceral leishmaniasis control actions. Thus, the present study analyzed some of these factors in a population of dogs in a Brazilian municipality, along with the limitations of control strategies implemented there. The association between the exposure variables and occurrences of infection was analyzed through logistic regression models. The disease control interventions were treated qualitatively. Out of the 755 animals examined, 13.6% (103/755) were seropositive. Of these, 23.3% (24/103) were asymptomatic and 76.7% (79/103) presented at least one clinical sign possibly associated with visceral leishmaniasis. With weak associations, purebred, shorthaired, over 5 years of age, male and large dogs were more prone to infection. The latter two variables formed the final regression model and the association with dog size was statistically significant. The control strategies developed presented limitations and a great number of seronegative dogs was culled. The data presented contribute towards better understanding of the dynamics of infection in canine visceral leishmaniasis and indicate that actions aimed towards adequate implementation of Visceral Leishmaniasis control program in Brazilian endemic areas should be prioritized.

The risk factors associated with canine visceral leishmaniosis (CVL) in Brazil are unclear and controversial. The objectives of this systematic review and meta-analysis were to identify the best evidence available in this field and to determine the gaps in existing knowledge. Literature searches were carried out using four databases, the reference lists within articles, and references provided by experts in the field. Theoretical discussions or separate and independent meta-analyses of p-values or of effect sizes were used to pool information about each variable. Thirty-six articles were selected for detailed review, including 31 cross-sectional, two ecological and three cohort studies. The variables showing significant association with CVL were short hair, purebred, peri-domestic restricted (as compared with domestic-restricted dogs), and presence of green areas adjacent to home. The occurrence of CVL was also associated with the presence of domestic fowl in the home environment, with free dogs (as compared with restrained dogs), with male gender and with dogs >1 or 2 years of age, although these associations were not statistically significant. Due to the small number of publications, consistent results could not be obtained concerning the role of other factors. Most studies did not describe the criteria of eligibility and the process of selection of participants in sufficient detail and employed only one diagnostic test as proof of infection. Few studies controlled for confounding variables. No statistical evidence of publication bias was detected, but a great deal of information contained in the primary articles was lost because the results were not adequately described. The results of this review contribute to a better understanding of CVL and should assist in optimizing the development and implementation of control policies. Continuous actions, prioritizing dogs at higher risk and areas with higher abundance of green vegetation, together with policies to promote responsible dog ownership are mandatory. Problems concerning study design and data analysis described in the present study need to be taken into consideration in future studies. These must follow clear procedures to select participants and utilize standardized, valid and reliable diagnostic methods. The development of multivariate models and the use of the STROBE statement for description of the results should also be encouraged. Further research should investigate the patterns identified and prioritize CVL-related factors that have not been fully recognized or elucidated. Finally, ecological and cohort studies of CVL and investigations in other countries of Latin America are urgently required., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Still today, more than 30 years after the beginning of the process of visceral leishmaniasis' urbanization, there is little knowledge about the risk factors for its occurrence, despite their relevance to the control and understanding of disease dynamics. The present study is the first systematic review with meta-analysis about factors associated with Leishmania infantum infection in humans in the Americas., Methods and Findings: After searching different databases, consultations to the reference lists of articles and to experts in the field, 51 studies were reviewed. Theoretical discussions or meta-analysis of p-values or of effect sizes were used to pool information about each variable. The Q test and the I(2) statistic were used to assess heterogeneities among the studies. Male sex was associated with visceral leishmaniasis in studies which used the leishmanin skin test for diagnosis and in those where the outcome was the clinical disease; the opposite occurred when serological diagnosis was applied. Younger individuals were less frequently infected than adults, but were more prone to illness. Although with different levels of evidence and of heterogeneity, the presence of dogs at home, higher dog seropositivity in nearby areas, lower socioeconomic status and highly vegetated areas were associated with L. infantum infection. This was not noticed for the presence of chickens in the house and with nutritional status. Susceptibilities to bias and limitations in the analysis and in the description of results were often identified in the studies analyzed., Conclusions: Results showed the existence of consistent patterns for some of the factors analyzed and should be taken into account in developing more effective and well-targeted control measures. Studies must be conducted in new areas of the continent, with improved methodological quality and prioritizing the investigation of the patterns identified and their causes, as well as variables for which knowledge is poor.