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Background Visceral leishmaniasis due to Leishmania infantum is currently spreading into new foci across Europe. Leishmania infantum transmission in the Old World was reported to be strongly associated with a few specific environments. Environmental changes due to global warming or human activity were therefore incriminated in the spread of the disease. However, comprehensive studies were lacking to reliably identify all the environments at risk and thereby optimize monitoring and control strategy. Methodology/Findings We exhaustively collected 328 cases of autochthonous visceral leishmaniasis from 1993 to 2009 in South-Eastern France. Leishmaniasis incidence decreased from 31 yearly cases between 1993 and 1997 to 12 yearly cases between 2005 and 2009 mostly because Leishmania/HIV coinfection were less frequent. No spread of human visceral leishmaniasis was observed in the studied region. Two major foci were identified, associated with opposite environments: whereas one involved semi-rural hillside environments partly made of mixed forests, the other involved urban and peri-urban areas in and around the region main town, Marseille. The two neighboring foci were related to differing environments despite similar vectors (P. perniciosus), canine reservoir, parasite (L. infantum zymodeme MON-1), and human host. Conclusions/Significance This unprecedented collection of cases highlighted the occurrence of protracted urban transmission of L. infantum in France, a worrisome finding as the disease is currently spreading in other areas around the Mediterranean. These results complete previous studies about more widespread canine leishmaniasis or human asymptomatic carriage. This first application of systematic geostatistical methods to European human visceral leishmaniasis demonstrated an unsuspected heterogeneity of environments associated with the transmission of the disease. These findings modify the current view of leishmaniasis epidemiology. They notably stress the need for locally defined control strategies and extensive monitoring including in urban environments., Author Summary As Leishmania infantum was reported to be spreading in Europe, we conducted an exhaustive collection of visceral leishmaniasis cases in Provence-Alpes-Cô te d′Azur, the most active focus in France, from 1993 to 2009. The analysis of the 328 cases showed no spread inside the study area and a three-fold decrease of yearly incidence notably because cases associated with AIDS became less frequent. Distribution of the disease showed two distinct foci strongly associated with specific environments. One focus, close to the border with Italy, was associated with areas characterized by scattered habitation and mixed forest in the foothills as previously acknowledged. Oppositely, the other focus was centered in urban areas of Marseille. These results modify our view on the epidemiology of visceral leishmaniasis in Europe by highlighting the ability of the parasite to spread into urban environments. These findings stress the need for continuation of monitoring and prevention efforts and demonstrate that control strategy should be locally defined.

Sand flies are recognised vectors of parasites in the genus Leishmania and a number of arthropod-borne viruses, in particular viruses within the genus Phlebovirus, family Bunyaviridae. In southern France, Toscana phlebovirus (TOSV) is recognized as a prominent cause of summer meningitis. Since Leishmania and TOSV have a common vector (Phlebotomus perniciosus), an epidemiologic link has been assumed for a long time. However, there is no scientific evidence of such a link between human leishmaniosis and phleboviral infections. To identify a possible link, we investigated the presence and distribution of antibodies against these two microorganisms (i) in individuals and (ii) at a spatial level in the city of Marseille (south-eastern France). Five hundred sera were selected randomly in the biobank of the Department of Parasitology of the Public Hospitals of Marseille. All sera were previously tested for IgG against Leishmania by Western Blotting, and TOSV IgG were detected by indirect immunofluorescence. The seropositivity rates were 21.4% for TOSV and 28% for Leishmania. Statistical analysis demonstrated that seropositivity for one pathogen was significantly associated with seropositivity to the other pathogen. This result provided the first robust evidence for the existence of an epidemiological relationship between Leishmania infantum and TOSV. Addresses of tested patients were geolocalized and integrated into Geographical Information System software, in order to test spatial relationship between the two pathogens. Spatial analysis did not allow to identify (i) specific patterns for the spatial distribution of positive serological results for TOSV or Leishmania, and (ii) a spatial relationship between Leishmania and TOSV positive serological results. This may reflect the fact that the sample studied was not powerful enough to demonstrate either a spatial clustering or co-location, i.e. that the actual risk exposure area is smaller than the mean of distance between patients in our study (245 m)., Author Summary Sand flies are tiny insects widely distributed in peri-Mediterranean countries where they can transmit Leishmania parasite and Toscana virus (TOSV). Since those microorganisms have a common vector, an epidemiologic link has been assumed for a long time. However, there is no scientific evidence of such a link between human leishmaniosis and phleboviral infections. To identify a possible link, we investigated the presence and distribution of antibodies to both Leishmania and TOSV in 500 sera of individuals living in Marseille, France. Antibodies are markers of past infections and reflect the exposition of population to pathogens. Statistical analysis demonstrated that seropositivity to one of these pathogens was significantly associated with seropositivity to the other pathogen. This result provided first robust evidence for an epidemiological relationship between Leishmania infantum and TOSV. Home addresses of tested patients were geolocalized in order to test spatial relationship between the two pathogens. This spatial analysis did not allow identifying either a spatial clustering or co-location, most probably because the sample was not powerful enough. Risk-factors of infection by TOSV (or Leishmania) would be investigated in seropositive patients' neighbourhood, in a range inferior to the mean of distance between patients in our study (245 meters).