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. 2022 Oct 7;16(10):e0010745. doi: 10.1371/journal.pntd.0010745

Leishmaniasis epidemiology in endemic areas of metropolitan France and its overseas territories from 1998 to 2020

Grégoire Pasquier 1, Magalie Demar 2, Patrick Lami 1, Asma Zribi 1, Pierre Marty 3, Pierre Buffet 4, Nicole Desbois-Nogard 5, Jean Pierre Gangneux 6, Stéphane Simon 2, Romain Blaizot 7, Pierre Couppié 7, Louis Thiebaut 1, Francine Pratlong 1, Jean-Pierre Dedet 1, Patrick Bastien 1, Yvon Sterkers 1, Christophe Ravel 1, Laurence Lachaud 1,*; Working Group for the Notification of Human Leishmanioses in France
Editor: David Soeiro Barbosa8
PMCID: PMC9624409  PMID: 36206322

Abstract

Background

In France, leishmaniasis is endemic in the Mediterranean region, in French Guiana and to a lesser extent, in the French West Indies. This study wanted to provide an updated picture of leishmaniasis epidemiology in metropolitan France and in its overseas territories.

Methodology/Principal findings

Leishmaniasis cases were collected by passive notification to the French National Reference Centre for Leishmaniases (NRCL) in Montpellier from 1998 to 2020 and at the associated Centre in Cayenne (French Guiana) from 2003 to 2020. In metropolitan France, 517 autochthonous leishmaniasis cases, mostly visceral forms due to Leishmania infantum (79%), and 1725 imported cases (French Guiana excluded), mainly cutaneous leishmaniasis from Maghreb, were recorded. A slight decrease of autochthonous cases was observed during the survey period, from 0.48 cases/100,000 inhabitants per year in 1999 (highest value) to 0.1 cases/100,000 inhabitants per year in 2017 (lowest value). Conversely, imported cases increased over time (from 59.7 in the 2000s to 94.5 in the 2010s). In French Guiana, 4126 cutaneous and mucocutaneous leishmaniasis cases were reported from 2003 to 2020. The mean incidence was 103.3 cases per 100,000 inhabitants/year but varied in function of the year (from 198 in 2004 to 54 in 2006). In Guadeloupe and Martinique (French West Indies), only sporadic cases were reported.

Conclusions/Significance

Because of concerns about disease expansion and outbreaks in other Southern Europe countries, and leishmaniasis monitoring by the NRCL should be continued and associated with a more active surveillance.

Author summary

Leishmaniasis is a disease due to a protozoan parasite and transmitted by sandfly. In France, this disease is endemic in the Mediterranean region, in French Guiana and to a lesser extent, in the French West Indies. We wanted to provide an updated picture of leishmaniasis epidemiology in metropolitan France and in its overseas territories. In metropolitan France, from 1998 to 2020, 517 autochthonous leishmaniasis cases, mostly visceral forms due to Leishmania infantum (79%), and 1725 imported cases (French Guiana excluded), mainly cutaneous leishmaniasis from Maghreb, were recorded. A slight decrease of autochthonous cases was observed during the survey period, from 0.48 cases/100,000 inhabitants per year in 1999 to 0.1 cases/100,000 inhabitants per year in 2017. Conversely, imported cases increased over time (from 59.7 in the 2000s to 94.5 in the 2010s). In French Guiana, 4126 cutaneous and mucocutaneous leishmaniasis cases were reported from 2003 to 2020. The mean incidence was 103.3 cases per 100,000 inhabitants/year but varied in function of the year (from 198 in 2004 to 54 in 2006). In Guadeloupe and Martinique (French West Indies), only sporadic cases were reported. Because of concerns about disease expansion and outbreaks, leishmaniasis monitoring should be continued and associated with a more active surveillance.

Introduction

Leishmaniasis is a vector-borne disease caused by Leishmania spp., an eukaryotic protozoan parasite belonging to the Trypanomastidae family transmitted by infected phlebotomine sandflies. Three main clinical presentations can be observed: cutaneous leishmaniasis (CL), mucocutaneous leishmaniasis (MCL), and visceral leishmaniasis (VL). According to the 2021 World Health Organisation report [1], leishmaniasis remains a major health problem in the Americas, East Africa, North Africa, West Asia, and South-East Asia. Indeed, in 2020, 208,357 CL cases, 12,838 VL cases, and 347 leishmaniasis-related deaths were reported worldwide [1]. However, due to underreporting, it was estimated in 2012 that 0.7 to 1.2 million CL cases, 0.2 to 0.4 million VL cases, and 20,000 to 40,000 leishmaniasis-related deaths occurred per year [2]. Updated data of 2017 [3] indicated a decrease in VL (50,000 to 90,000 estimated cases).

In France, leishmaniasis is endemic in the Mediterranean part of metropolitan France, in French Guiana, and to a lesser extent in the French West Indies. Many imported cases also are recorded. Between 1999 and 2012, the incidence of endemic leishmaniasis in the South of France was 0.21 per 100,000 inhabitants (i.e. a mean number of 22.6 cases per year) [4], and the most common notified clinical form was VL (84.5%). Five endemic foci were described: Pyrénées-Orientales, Cévennes, Provence, Côte d’Azur, and Corsica [5]. Infections seem to occur in two distinct environments: semi-rural hillsides with mixed forests, and the urban/peri-urban region of Marseille [6]. Leishmania infantum is the only species involved in the autochthonous leishmaniasis cases in France. The sandfly vectors include Phlebotomus perniciosus, the most common, and Phlebotomus ariasi, mainly in the Cévennes and Pyrénées-Orientales foci [7]. These vectors have a seasonal period of activity between June and October [8]. The principal animal reservoir host is the domestic dog (Canis familiaris). A review that analysed data on 39,259 tested dogs [9] reported a mean canine seroprevalence of 8%; however, higher seroprevalence (29.6%) was observed in the Cévennes focus [10]. In the same study, PCR screening detected the parasite presence in 79.8% of screened dogs that were either asymptomatic or had canine leishmaniasis. The place of other reservoir hosts, such as red foxes (Vulpes vulpes) and cats (Felis catus), has been mentioned but remains anecdotal [11].

French Guiana and the French West Indies, two French territories on the American continent, also are endemic areas. In French Guiana, previous studies in 1990 [12] and 2001 [13] reported an incidence of approximately 200 cases/100,000 inhabitants per year, whereas a more recent publication described an incidence of 56 cases/100, 000 inhabitants per year between 2006 and 2013 [14]. Infections follow a seasonal pattern: the highest number of cases is diagnosed in January and the lowest in August [14]. A time series analysis showed that an increase in rainfall is associated with a decrease in the leishmaniasis cases diagnosed two months later [15]. Five species of Leishmania are involved: Leishmania guyanensis, Leishmania braziliensis, Leishmania amazonensis, Leishmania lainsoni and Leishmania naiffi, by decreasing order of prevalence [16]. The digenetic cycle is well known for L. guyanensis where the vector is the arboreal phlebotomine Lutzomyia umbratilis and the primary reservoir is the two-toed sloth Choloepus didactylus [17]. For the other Leishmania species, reservoirs are less established: L. naiffi has been associated with the nine-banded armadillo (Dasypus novemcinctus), L. lainsoni with the agouti rodent (Dasyprocta spp.), and L. amazonensis with the rodent Proechimys cuvieri [16]. Only MCL and CL have been described in these overseas regions. L. braziliensis and to a lesser extent L. guyanensis infections have been associated with MCL [17] that can cause destructive lesions of the nasal and oropharyngeal/laryngeal mucosa [18]. L. naiffi infections are often acquired during leisure activities in anthropized coastal areas, whereas infections by the other species are contracted mainly in primary forest regions, during professional activities (soldiers, gold miners) [17]. In the French West Indies (mainly Martinique and Guadeloupe), autochthonous CL and VL cases are sporadically reported [19]. Both L. infantum and Leishmania martiniquensis are present and both may cause VL [19,20]. The vector is supposed to be Lutzomyia atroclavata and the animal reservoir could be black rats (Rattus rattus), mongooses (Herpestes auropunctatus), marsupials (Didelphis marsupialis), and dogs [16].

A surveillance system that covers the South of France, French Guiana and French West Indies was implemented in 1998 with the creation of the French National Reference Centre for Leishmaniases (NRCL) in Montpellier and the associated centre in Cayenne, French Guiana. One of NRCL missions is the epidemiologic monitoring of autochthonous and imported leishmaniasis cases in metropolitan France, French Guiana, and French West Indies. The surveillance system is based on passive and voluntary notification by the medical laboratories or physicians involved in the diagnosis. Each year, these data are analysed and the report is sent to Santé Publique France (the French public health agency).

The aim of the present study was to accurately describe leishmaniasis epidemiology in metropolitan France, French Guiana and West French Indies based on the data collected by the NRCL in 22 years (from 1998 to 2020). The data analysis allowed determining the patients’ age, sex, place of contamination, and number of lesions and location (for CL).

Methods

Ethics statement

Human biological samples and the associated data sent to the French NRCL are registered and declared for research purposes as a biobank for the Centre Hospitalier de Montpellier and the French National Institute of Health Surveys. No institutional review board approval is required according to the French legislation (article L. 1111–7 du Code de la Santé Publique, article L. 1211–2 du Code de Santé Publique, articles 39 et suivants de la loi 78–17 du 6 janvier 1978 modifiée en 2004 relative à l’informatique, aux fichiers, et aux libertés).

Data collection

Cases of leishmaniasis were reported to the NRCL by more than 200 sources: university hospitals, general hospitals, health service of the French army, medical laboratories, and general practitioners. The reporting form is available at the following link: https://cnrleish.edu.umontpellier.fr/files/2018/04/Declaration_pub_2011.pdf. The collected data include: age, sex, past medical history especially causes of immunosuppression (HIV, haematological malignancy, solid organ transplant, immunosuppressive therapy, primary immune deficiency), presumed place of contamination, name of the reporting centre, clinical (e.g. number and localization of lesions) and laboratory parameters, method of diagnosis (direct examination, culture, serology, PCR), and species identification if available. Forms are completed anonymously and are analysed in the framework of NRCL public health mission, in cooperation with Santé Publique France. Cases were defined as patients with clinical signs and symptoms compatible with at least one positive laboratory test (direct microscopic examination, culture, serology, or real-time PCR). Then, the collected cases were checked and validated by a senior parasitologist before addition to the database. For this study, data collected from 1998 to 2020 (for metropolitan France) and from 2003 to 2020 (for French Guiana and French West Indies) were used.

Biological diagnosis was performed according to the protocols in use in each center: direct examination, culture, PCR (and serology for VL). Species identification was based on MLEE or molecular method or MALDI-TOF.

Statistical analysis

The incidence of autochthonous leishmaniasis was calculated using demographic data from the Institut national de la statistique et des études économiques, https://www.insee.fr/; French national institute of statistics and economic studies). The patients’ characteristics were expressed as mean (95% Confidence Interval). Multiple pairwise comparisons (pairwise Wilcoxon test) were performed after a significant global test (for quantitative data, ANOVA test if the ANOVA hypotheses were fulfilled, otherwise Kruskal-Wallis test; Fisher’s exact test for categorical data). Changes in proportion and incidence over time were assessed by the Cochran-Armitage test for trend. For French Guyana, Chi square test was used to compare relative incidences of leishmaniasis in inland and coastal localities. Statistical analyses were done with the R 3.6.0 software.

Map design

Maps were designed with the Articque software (https://www.articque.com).

Results

From 1998 (2003 for French Guyana) to 2020, 6379 leishmaniasis cases were notified to the NRCL (Fig 1): autochthonous leishmaniasis in metropolitan France (n = 517), in French Guiana (n = 4126), and in the French West Indies (n = 11), and also imported leishmaniasis cases from other endemic countries (n = 1725).

Fig 1. Number of reported cases to the French National Reference Centre for Leishmaniasis by year.

Fig 1

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Concerning the autochthonous leishmaniasis cases in metropolitan France (n = 517; only caused by L. infantum), the men to women ratio was 1.89. The mean incidence in the endemic departments (mainly Alpes-Maritimes, Var, Bouches-du-Rhône, Gard, Hérault and Pyrénées-Orientales) (Fig 2) was 0.26 cases per 100,000 inhabitants/year, and the mean number of cases per year was 22.5 for a population pool of ~9,000,000 inhabitants. The incidence tended to decrease over time from a maximum of 0.48 cases/100,000 inhabitants per year in 1999 to a minimum of 0.1 cases/100,000 inhabitants per year in 2017 (p<0.001) (Fig 1). This reduction should be appraised relative to the decreasing percentage of patients living with HIV (from 53% in 1998 to 9% in 2020; p<0.001) (S1 Fig). The main clinical form was VL (79%, 407/513), followed by CL (18%, 91/513) and MCL (3%, 15/513). Patients with VL were younger than patients with CL and with MCL (35 (32.7–37.3) versus 43.7 (38.2–49.3) versus 61.8 (55.9–67.7) years, respectively; p<0.001) (S2 Fig). Among the patients with VL, 45% (163/385) were immunosuppressed mainly because of HIV infection (31%, 118/385), immunosuppressive treatment (8%, 29/385), blood malignancies (4%, 16/385), and solid organ transplantation (2%, 9/385). Among the non-immunosuppressed patients with VL, 40% (84/212) were <6-year-old children (S3 Fig).

Fig 2. Distribution of the endemic leishmaniasis cases reported in metropolitan France by département (i.e.

Fig 2

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French administrative regions) from 1998 to 2020 (n = 380; for 137 others cases département of contamination was missing). Maps were designed with the Articque software (https://www.articque.com).

Most of the diagnosed cases in metropolitan France were imported (n = 1725): 53% (n = 910) from Maghreb, 19% (n = 327) from Central/South America (French Guiana excluded), 15% (n = 265) from sub-Saharan Africa, 8% (n = 133) from Southern Europe, 3% (n = 51) from the Eastern Mediterranean countries (Turkey, Syria, Israel, Jordania) and Georgia, 1% (n = 21) from the Middle East, 1% (n = 13) from Central Asia, and <1% (n = 5) from South Asia (Fig 3). CL was the most frequently encountered clinical form (89%, n = 1542), followed by VL (10% n = 167) and MCL (1% n = 10). The men to women sex ratio was 1.51. The mean number of declared cases per year tended to increase from 59.7 in the 2000s to 94.5 in the 2010s (p>0.001)(Fig 1). Analysis of the species implicated in CL showed that for cases imported from Maghreb, L. major was predominant (470/584, 80%) followed by L. infantum (62/584, 12%), Leishmania tropica (31/584, 5%) and Leishmania killicki (21/584, 4%) (Fig 4). L. major was predominant also in cases from sub-Saharan Africa (152/166, 92%), whereas L. tropica was dominant in case from the Eastern Mediterranean countries (17/27, 55%). Concerning the imported cases from the New World (French Guiana excluded), L. guyanensis (136/223, 61%) was the most frequently identified species, followed by L. braziliensis (64/223, 29%), and Leishmania mexicana (14/223, 6%). For cases from the Old World (metropolitan France included), L. major was more associated with multiple lesions (389/580, 67%) than L. killicki (5/19, 26%, p = 0.001), L. tropica (25/61, 41%, p<0.001) and L. infantum (38/142, 27%, p<0.001). Conversely, L. major was associated with fewer face lesions (98/494, 20%) than L. killicki (10/17, 59%, p = 0.001), L. tropica (30/55, 55%, p<0.001) and L. infantum (76/128, 59%, p<0.001).

Fig 3. Origin of the imported leishmaniasis cases in metropolitan France, French Guiana, and French West indies (1998–2020).

Fig 3

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Maps were designed with the Articque software (https://www.articque.com).

Fig 4. Distribution of Leishmania species according to the place of transmission from 1998 to 2020).

Fig 4

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(n = 3393, for 2986 other cases species was missing) Maps were designed with the Articque software (https://www.articque.com).

Imported MCL cases (n = 10) were caused by L. braziliensis (n = 4 from Central/South America) and L. infantum (n = 4 from Southern Europe and n = 2 from Maghreb). The mean age was 48.3 (41.5–55.1) years.

Imported VL cases (n = 167) were mostly due to infection by L. infantum (94%) and by Leishmania donovani (6%). Patients mainly contracted the disease in Southern Europe (n = 86, 52%), Maghreb (n = 42, 25%) and sub-Saharan Africa (n = 26, 16%). Their mean age was 38.6 (35.3–41.9) years; 55% of patients were immunocompetent and among them only 26% (22/86) were younger than 6 years of age. In immunosuppressed patients, the causes were HIV (48/71, 68%), immunosuppressive therapy (13/71, 18%), and solid organ transplantation (7/71, 10%).

From 2003 to 2020, 4126 cases of cutaneous and mucocutaneous leishmaniasis were caused by infection in French Guiana (diagnosed in French Guiana or in metropolitan France). The mean incidence was 103.3 cases per 100,000 inhabitants/year and the mean number of declared cases per year was 229 for a mean population of 238,000 inhabitants (Fig 1). The incidence has decreased slightly over time (p<0.001). The men to women ratio was 4.15. No VL case was reported, and MCL cases were exceptional (n = 7). Among the 1969 cases with identified species, L. guyanensis was the most frequently detected (85%), followed by L. braziliensis (10%), L. amazonensis (3%), L. lainsoni (2%), and L. naiffi (1%). Leishmaniasis cases were less frequent in littoral localities than the in the inland territories and the area along the two main rivers (Oyapoque at the Brazil border and Maroni at the border with Surinam) (Fig 5). Analysis of the data on CL cases from the New World (French Guiana and the rest of Central and South America) showed that patients infected by L. guyanensis were more prone to develop multiple lesions (453/913, 50%) compared with those infected by L. braziliensis (34/131, 26%, p<0.001) and L. naiffi (1/12, 8%, p = 0.046).

Fig 5. Distribution of the reported leishmaniasis cases in French Guiana by locality from 2003 to 2020).

Fig 5

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(n = 2193, for others 1933 cases, locality was missing) Maps were designed with the Articque software (https://www.articque.com).

In the French West Indies, only few cases were reported. In Guadeloupe, three CL cases and one VL case by L. infantum were notified. In Martinique, four CL cases by L. martiniquensis and two VL cases, including one caused by L. martiniquensis, were recorded. In Saint Martin, one CL case caused by L. martiniquensis was recorded.

Discussion

The creation of the NRCL has allowed the establishment of a surveillance system for indigenous and imported leishmaniasis cases in France. The University Hospital of Cayenne located in French Guiana, a French territory in South America and a leishmaniasis endemic area, has been a NRCL privileged partner for 20 years. This study described and analysed the data collected by the NRCL in 23 years of leishmaniasis surveillance in metropolitan France and overseas territories (n = 6379 cases notified).

In metropolitan France, the incidence of autochthonous cases, mainly VL due to L. infantum, decreased from 0.46 in 1999 to 0.1 in 2017 in the hypoendemic area (French Mediterranean coast). This could be linked to the concomitant decrease of patients with HIV and VL (from more than 50% of all leishmaniosis cases in 1998 to less than 10% in 2020) due to the wide implementation of antiretroviral therapy [6]. A similar reduction in leishmaniasis-HIV co-infections was observed in other Southern European countries [21]. On the other hand, no consistent increase of leishmaniasis cases in non-HIV immunosuppressed patients due to new immunosuppressive therapies was observed. The paediatric population (<8 years of age) accounted for half of VL cases in 1986–1987 [22], but only for 24% between 1998 and 2020. Cases in immunocompetent adults represented between 11% and 63% of all reported VL cases, in function of the year. The decline of VL cases may also be partly linked to the widespread use of insecticide-impregnated collars [23] and the anti-leishmaniasis vaccine [24] to control the canine reservoir. The role of human asymptomatic carriers has been suggested, but evidence is lacking [25]. However, some studies suggested that VL foci are distributed more in function of the vector presence than of the canine reservoir density [6]. This rises the concern of the northward spread of phlebotomine vectors caused by global warming [26]. Some authors have warned of possible transmission of leishmaniasis outside Mediterranean coast such as in the Jura [27] but it remained exceptional. Cases of autochthonous CL or MCL were rare, because L. infantum tropism is essentially visceral; however, benign cutaneous forms might be frequently underreported because most of the time they heal spontaneously.

Concerning the imported leishmaniasis cases in metropolitan France (French Guiana excluded), they were predominantly CL caused by L. major and L. tropica (cases from Maghreb and sub-Saharan Africa) and by L. guyanensis and L. braziliensis (when imported from South America). The mean number of cases reported per year was 75, with an increase from 15 in 1998 up to 165 in 2019. The first hypothesis is that we have improved the reporting system, the second is that it is possible that there have been changes in migration flows, but we do not have data on this subject. Stays in the Maghreb accounted for 53% (n = 910) of imported cases, another hypothesis would be the increase in vacation trips to this region. In the Old World, 67% of patients with CL due to L. major presented multiple lesions, but the face was less concerned compared with other species. This may be of clinical importance because the number and localization of lesions might influence the treatment [3]. These data could be used to revise treatment protocols and to refine the recommendations due to the frequency of multiple lesions [28]. Cases of imported VL due to L. infantum were mostly acquired in Southern Europe and Maghreb and accounted only for 10% of all imported cases.

French Guiana, a French territory located in South America, is an endemic zone of cutaneous and mucocutaneous leishmaniasis. The mean incidence was 103.3 cases per 100,000 individuals/year), but it varied in function of the year (from 54 in 2004 to 198 in 2006). This variability may be partly explained by the negative correlation between annual rainfall and number of CL cases [15]. Moreover, most of cases were reported from inland localities, although the population lives mainly along the coastal area (p<0.001). A multicentric prospective study [29] reported that Brazilians represented 59.3% of infected people, mostly gold miners. We can hypothesize that this is one of the reasons that could explain the men to women sex ratio of 4.15 found in French Guiana compared with 1.89 in metropolitan France. The illegal migration of Brazilian gold diggers has been also associated with L. braziliensis emergence (from 8.9% in 2006 to 13.0% in 2013) [14]. Indeed, in data from the 1980s, L. braziliensis was absent in French Guiana [30]. Moreover, more recently, it was demonstrated that L. braziliensis infections are more common in locality with gold mines [14]. However, the NRCL data did not confirm the spread of L. braziliensis after 2013. As previously reported [29], patients infected by L. guyanensis were more likely to develop multiple lesions compared to those infected by L. braziliensis. The precise species identification is crucial for therapeutic adaptation because treatment differs for the two main species in this region: L. guyanensis (pentamidine) and L. braziliensis (meglumine antimoniate or amphotericin B) [31]. L. naiffi was associated with unique lesions, as previously described [17], and with a mild clinical course. The identified risk factors of CL were: living in traditional wooden houses, trips in primary forests, proximity to spring water, and presence of dogs around the house [29]. The other leishmaniasis forms were very uncommon (n = 7 MCL cases in 17 years) or absent (autochthonous VL).

In the French West Indies, leishmaniasis is autochthonous in Martinique, Guadeloupe, and Saint Martin. Sporadic CL and VL cases caused by L. infantum and L. martiniquensis were reported [19].

Some limitations linked to how data are collected must be acknowledged. The passive surveillance implemented by the NCRL induces underreporting bias compared with active surveillance (17% of underreporting for VL) [6]. Moreover, some data were frequently missing in the reporting forms (lack of species identification in 46% of cases, and absence of clinical information on the number of lesions for 62% of CL cases). Nevertheless, the analysis of national data over a long period of time has updated and shed new light on the epidemiology of leishmaniasis in France. These results bring moderate concerns about leishmaniasis expansion due to global warming, and highlight the importance of a national surveillance system, such as the NCRL, and of more proactive reporting. Indeed, active notification with direct phone calls to laboratories concerned is more effective but requires more human resources [6]. Future challenges will be to complement these data with epidemiological field studies, for example to monitor canine leishmaniasis and vector distribution in the South of France.

Supporting information

S1 Fig. Immune profiles among the patients with visceral leishmaniasis in metropolitan France (n = 385; missing data = 22).

(TIF)

Click here for additional data file. (389KB, tif)
S2 Fig. Age of patients according to the leishmaniasis clinical form in metropolitan France (n = 509; 8 missing data); red, mean ± standard deviation.

CL: Cutaneous Leishmaniasis; MCL: Muco-Cutaneous Leishmaniasis; VL: Visceral Leishmaniasis.

(TIF)

Click here for additional data file. (406.1KB, tif)
S3 Fig. Age of patients with visceral leishmaniasis according to the immunosuppression type in metropolitan France (n = 403; 4 missing data); red, mean ± standard deviation.

SOT: Solid Organ Transplant; NA: No data Available.

(TIF)

Click here for additional data file. (713.8KB, tif)
S1 Table. Number of cutaneous leishmaniasis cases with unique and with multiple lesions according to the causative species.

(DOCX)

Click here for additional data file. (13.7KB, docx)
S2 Table. Number of cutaneous leishmaniasis cases with lesions involving the face according to the species involved.

(DOCX)

Click here for additional data file. (13.9KB, docx)

Acknowledgments

The Working Group for the Notification of Human Leishmanioses in France (In alphabetical order and in addition to the main authors) Y Balard (Centre National de Référence des Leishmanioses, Montpellier), P Delaunay and C Pomares (CHU Nice), S Hamane (CHU Saint Louis, Paris), H Yéra (CHU Cochin, Paris), F Foulet (CHU de Créteil), S Houzé (CHU Bichat, Paris), X Iriart (CHU de Toulouse), A Izri (CHU Avicenne, Paris), E Lightburne (Services de Santé des Armées Lavéran, Marseille), Méja Rabodonirina (CHU de Lyon), Coralie L’Ollivier (CHU La Timone, Marseille), Gloria Morizot (Institut Pasteur, Paris), Tiphaine Merguey (CHU de Rennes), Renaud Piarroux (CHU La Timone, Marseille) We warmly thank all the centres that notified leishmaniasis cases to the NRCL over the years, and regret not to be able to name all our correspondents individually.

We thank Pr Nicolas Nagot and Dr Lionel Moulis for their assistance in statistical analysis.

Data Availability

All relevant data are within the manuscript and its Supporting Information files.

Funding Statement

The authors received no specific funding for this work.

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PLoS Negl Trop Dis. doi: 10.1371/journal.pntd.0010745.r001

Decision Letter 0

Marcelo U Ferreira, David Soeiro Barbosa

25 Feb 2022

Dear Dr Lachaud,

Thank you very much for submitting your manuscript "Leishmaniasis epidemiology in endemic areas of metropolitan France and its overseas territories from 1998 to 2020" for consideration at PLOS Neglected Tropical Diseases. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. In light of the reviews (below this email), we would like to invite the resubmission of a significantly-revised version that takes into account the reviewers' comments.

Major revision is necessary before to be considered for publication. See more detailed reviewers comments and questions below. Please, reply or justify each of the questions/comments.

We cannot make any decision about publication until we have seen the revised manuscript and your response to the reviewers' comments. Your revised manuscript is also likely to be sent to reviewers for further evaluation.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to the review comments and a description of the changes you have made in the manuscript. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Please prepare and submit your revised manuscript within 60 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email. Please note that revised manuscripts received after the 60-day due date may require evaluation and peer review similar to newly submitted manuscripts.

Thank you again for your submission. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

David Soeiro Barbosa

Associate Editor

PLOS Neglected Tropical Diseases

Marcelo Ferreira

Deputy Editor

PLOS Neglected Tropical Diseases

***********************

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: The study has a clear objective. However, the methods applied in data analysis do not support most of the discussions and conclusions carried out in the study. Authors must demonstrate their data in relation to the 95% Confidence Interval and not to one standard deviation. A Time Series Analysis must be performed so that statements related to possible trends observed in the study have statistical validity.

Reviewer #2: -Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

Yes

-Is the study design appropriate to address the stated objectives?

Yes

-Is the population clearly described and appropriate for the hypothesis being tested?

Yes

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

Yes

-Were correct statistical analysis used to support conclusions?

Yes

-Are there concerns about ethical or regulatory requirements being met?

Yes

Reviewer #3: This article aims to update the epidemiological situation of leishmaniasis in metropolitan France and its overseas territories. The authors uses existing passive surveillance system established for indigenous and imported leishmaniasis cases in the country. The statistical methods used to analyze the available data and address the objectives of the study is appropriate.

--------------------

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: The results are well presented, but they are mostly described data, without entering into some kind of spatio-temporal pattern. Thus, many discussions are not supported by the data presented.

Ex1: This may be due to new migratory dynamics and/or to the improvement of the notification system. Sojourns in

the Maghreb region were at the origin of 53% (n=910) of imported cases (53%, n=910).

Ex2: A multicentric prospective study (28) reported that Brazilians represented 59.3% of infected people, mostly gold

miners. This could explain the men to women sex ratio of 4.15 found in French Guiana compared with 1.89 in metropolitan France.

The study states that a reduction in incidence from 0.48 to 0.1 is a slight reduction. Depending on the graphic scale, it may seem small, but in proportional terms it is a reduction of 4.8 times. Is it statistically different? The time series decomposition could state whether the trend is decreasing or stability.

Reviewer #2: - Does the analysis presented match the analysis plan?

Yes

-Are the results clearly and completely presented?

The reviewer suggests an implementation on the presentation of results

-Are the figures (Tables, Images) of sufficient quality for clarity?

Yes

Reviewer #3: The results and analyses are clearly presented.

--------------------

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: Many of the conclusions and discussions of the study are made from data that were not generated by the study or are not supported by the data presented. For example: This is related to the return from holydays in this region.

The authors make the following statement:Moreover, cases showed a spatial heterogeneity.

What result or analysis can support this discussion? Only the visualization of maps would not allow this statement. Clustering analyses, such as Moran's Index, Moran's Local Index or spatial scanning should be used, if any discussion related to heterogeneity wants to be carried out.

Second paragraph of the discussion, at the beginning only reaffirms results, without discussing.

Page 19: Concerning the clinical features, L. guyanensis was more often associated with multiple cutaneous lesions than L.

braziliensis, as mentioned elsewhere (28). Review the sentence. In some parts of the text the percentage value - such as 10%, is displayed twice.

The authors make the following statement: Nevertheless, the analysis of data over a long period of time allowed a reliable

assessment of the disease spatiotemporal changes. A descriptive analysis of the data does not support this result. The temporal analysis was discussed in a descriptive way. And the spatial analysis was performed only with thematic maps. A spatiotemporal pattern analysis should be conducted.

Reviewer #2: -Are the conclusions supported by the data presented?

Yes

-Are the limitations of analysis clearly described?

Yes

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

Yes

-Is public health relevance addressed?

Yes

Reviewer #3: The conclusion is supported by the data and analysis. The limitation of the data and analysis is clearly described. The paper also pinpoints the potential use of the presented information for public health measures.

--------------------

Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: There is a need for changes in methodology and analysis, so that the results are more clearer and the study discussions are related to its findings. Therefore, my opinion is for the rejection of the paper, requesting that changes be made in the structure of the document, for a future new submission in the journal.

Reviewer #2: (No Response)

Reviewer #3: This paper presents important epidemiological updates about the status of leishmaniasis (Cutaneous; Mucocutaneous and visceral forms), parasite species, demographic characteristics and their distributions despite the limitedness of data availability and use of a passive surveillance data. The authors may consider the following minor edits:

The term Tegumentary leishmaniais is less commonly used and not very well understood especially in the old world. Therefore, please consider replacing by cutaneous and mucocutaneous leishmaniasis where ever it's used in the manuscript.

The leishmaniasis situation in traditionally non-endemic areas of metropolitan France has not been highlighted or discussed; however, as the paper attempts to discuss expansion of leishmaniasis, its important to include some updates in this regard, e.g., reports of leishmaniasis in the Jura region..

Place of contamination ...in this paper is used as place of origin of infection or disease. Whereas in English as this could be confusing and as its commonly used, it's preferred to use ..Place where infection or disease acquired, Place where infection/disease contracted or place of transmission;

Please replace Near East by middle east or the exact countries referred as this term is not standard and no more used and may not be understood by many readers of the article/journal. For the titles of the figures, e.g., Fig 4, 5 .. consider replacing 'repartition' by 'distribution' ....

On page 18, last sentences of the second paragraph, please consider rephrasing as follows : These data could be used to revise treatment protocols and .....

--------------------

Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: The greatest strength of the study is a large database, with very important information in the understanding of leishmaniasis. The weakness of the study is that it does not apply a methodology that supports the discussions presented.

Reviewer #2: The manuscript on the "Leishmaniasis epidemiology in endemic area of metropolitan France and its overseas territories from 1998 to 2020" is very interesting and well structured. However, the presentation of data and its analysis sometimes appears incorrect because the missing /incomplete data are not reported. For the section Results missing data are reported only in the Supporting Information. For this the reviewer proposes to improve methods and results.

The manuscript is for “Minor Revision”.

Specific comments

Pag. 4, Line15: Correct “The animal reservoir host…” in “The principal animal reservoir host…”.

Pag. 6, Lines 8-16: The AA should briefly summarise the methods used for human diagnosis and Leishmania species identification. The link for the reporting form is important but it is difficult to the readers look for the specific diagnostic details and methods applied.

Pag. 6, Lines 16-19: As suggested by WHO, diagnosis of VL and CL are different. VL diagnosis is a combination of a parasitological (microscopic, culture or molecular) and a serological technique. In addition, the AA don’t give any information about the diagnostic gene/s primers for real-time PCR.

Results: In the whole section missing data are not reported in the manuscript text except in the Supporting Information. The AA should improve the manuscript text furnishing both missing and incomplete data in the results. Similarly, the total of Leishmania species identification samples (strains and bioptic samples) should be indicated.

Pag. 9, Lines 4 and 13: the geographical term of Near East is often overlapping with Middle East. Middle East is the geographical area better identified therefore the AA should clarify (as reported in the map) regions remaining in the Near East.

Refs 16 and 17. The AA should check these 2 references because they appear reverse as citation in the text (Pags 9 and 10).

Reviewer #3: This article aims to update the epidemiological situation of leishmaniasis in metropolitan France and its overseas territories. Considering the limitation of the passive surveillance, the paper has analysed and presented the trend in the three forms of the disease over the years, the distribution of cases and parasite species over the geographic areas focusing mainly on the endemic areas and available demographic variables. As the paper attempts also to discuss the potential expansion of the disease with changing environmental and climatic changes, its important to include some highlights/reports from non-endemic areas and also to elaborate on how or what type of active surveillance can be implemented as this is one of their final conclusion and recommendation.

--------------------

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PLoS Negl Trop Dis. doi: 10.1371/journal.pntd.0010745.r003

Decision Letter 1

Marcelo U Ferreira, David Soeiro Barbosa

16 Aug 2022

Dear Dr Lachaud,

We are pleased to inform you that your manuscript 'Leishmaniasis epidemiology in endemic areas of metropolitan France and its overseas territories from 1998 to 2020' has been provisionally accepted for publication in PLOS Neglected Tropical Diseases.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests.

Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated.

IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript.

Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS.

Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.

Best regards,

David Soeiro Barbosa

Academic Editor

PLOS Neglected Tropical Diseases

Marcelo Ferreira

Section Editor

PLOS Neglected Tropical Diseases

***********************************************************

Please, include changes or justify considering the new suggestions.

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: -Are the objectives of the study clearly articulated with a clear testable hypothesis stated? YES

-Is the study design appropriate to address the stated objectives? YES

-Is the population clearly described and appropriate for the hypothesis being tested? YES

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested? YES

-Were correct statistical analysis used to support conclusions? YES

-Are there concerns about ethical or regulatory requirements being met? YES

Reviewer #3: (No Response)

**********

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: -Does the analysis presented match the analysis plan? YES

-Are the results clearly and completely presented?

I suggest changing the term slight in lines 221 and 318.

In line 359 the authors used the term "it hugely varied", in percentages that are very similar.

-Are the figures (Tables, Images) of sufficient quality for clarity? YES

Reviewer #3: (No Response)

**********

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: All requested changes have been made and the conclusion is adequate.

Reviewer #3: (No Response)

**********

Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: The requested changes are very specific. I entered MINOR REVISION, but it could be ACCEPTED.

I believe that in percentage terms the term slight is not adequate. Readers of the article may start to replicate the term SLIGHT, without understanding the percentage context in future citations of the paper, which in my view is an inadequate understanding of the epidemiological change from 0.46 to 0.1.

Reviewer #3: (No Response)

**********

Attachment

Submitted filename: Revised manuscript_V8_clean.docx

Click here for additional data file. (2.3MB, docx)
PLoS Negl Trop Dis. doi: 10.1371/journal.pntd.0010745.r004

Acceptance letter

Marcelo U Ferreira, David Soeiro Barbosa

23 Sep 2022

Dear Pr Lachaud,

We are delighted to inform you that your manuscript, "Leishmaniasis epidemiology in endemic areas of metropolitan France and its overseas territories from 1998 to 2020," has been formally accepted for publication in PLOS Neglected Tropical Diseases.

We have now passed your article onto the PLOS Production Department who will complete the rest of the publication process. All authors will receive a confirmation email upon publication.

The corresponding author will soon be receiving a typeset proof for review, to ensure errors have not been introduced during production. Please review the PDF proof of your manuscript carefully, as this is the last chance to correct any scientific or type-setting errors. Please note that major changes, or those which affect the scientific understanding of the work, will likely cause delays to the publication date of your manuscript. Note: Proofs for Front Matter articles (Editorial, Viewpoint, Symposium, Review, etc...) are generated on a different schedule and may not be made available as quickly.

Soon after your final files are uploaded, the early version of your manuscript will be published online unless you opted out of this process. The date of the early version will be your article's publication date. The final article will be published to the same URL, and all versions of the paper will be accessible to readers.

Thank you again for supporting open-access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.

Best regards,

Shaden Kamhawi

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

Paul Brindley

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Fig. Immune profiles among the patients with visceral leishmaniasis in metropolitan France (n = 385; missing data = 22).

    (TIF)

    Click here for additional data file. (389KB, tif)
    S2 Fig. Age of patients according to the leishmaniasis clinical form in metropolitan France (n = 509; 8 missing data); red, mean ± standard deviation.

    CL: Cutaneous Leishmaniasis; MCL: Muco-Cutaneous Leishmaniasis; VL: Visceral Leishmaniasis.

    (TIF)

    Click here for additional data file. (406.1KB, tif)
    S3 Fig. Age of patients with visceral leishmaniasis according to the immunosuppression type in metropolitan France (n = 403; 4 missing data); red, mean ± standard deviation.

    SOT: Solid Organ Transplant; NA: No data Available.

    (TIF)

    Click here for additional data file. (713.8KB, tif)
    S1 Table. Number of cutaneous leishmaniasis cases with unique and with multiple lesions according to the causative species.

    (DOCX)

    Click here for additional data file. (13.7KB, docx)
    S2 Table. Number of cutaneous leishmaniasis cases with lesions involving the face according to the species involved.

    (DOCX)

    Click here for additional data file. (13.9KB, docx)
    Attachment

    Submitted filename: Responses to the Reviewers.docx

    Click here for additional data file. (30.5KB, docx)
    Attachment

    Submitted filename: Revised manuscript_V8_clean.docx

    Click here for additional data file. (2.3MB, docx)

    Data Availability Statement

    All relevant data are within the manuscript and its Supporting Information files.

    Articles from PLOS Neglected Tropical Diseases are provided here courtesy of PLOS

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