Leishmaniosis of companion animals in Europe: An update

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Leishmaniosis of companion animals in Europe: An update Maria Grazia Pennisi ∗ Dipartimento di Scienze Veterinarie, University of Messina, Polo Universitario Annunziata, 98168 Messina, Italy

a r t i c l e

i n f o

Keywords: Companion animals Dog Cat Leishmania Sand flies Europe

a b s t r a c t Leishmaniosis caused by Leishmania infantum is a vector-borne zoonotic disease endemic in southern Europe, but which is spreading northwards. Millions of dogs, cats and other non-conventional companion animals susceptible to L. infantum, living in European households, may develop a severe disease and contribute to the spread of leishmaniosis because of travelling or re-homing. Dogs are the main reservoir but other new reservoirs have recently been incriminated. Sand flies remain the sole proven vector and non-vectorial transmission has been reported at individual level and in areas where the vector is absent. Clinical disease affects only a proportion of infected dogs and a complex genetic background of immune response is responsible for this susceptibility. There is a wide range of serological and parasitological diagnostic tools available whose cost-effective use depends on a reasoned approach. Clinical response to treatment of sick dogs is variable. Clinical cure is often obtained but clinical recurrence can occur and post-therapy follow up should be maintained life-long. In Europe, vaccination can be combined with individual protection with pyrethroids as part of an integrated approach to prevention. L. infantum is the only species isolated from cats in Europe and xenodiagnosis substantiated that infected cats are infectious for sand flies. Feline infection may be frequent in endemic areas, but prevalence is generally lower than in dogs. When cats are tested by both serological and molecular techniques discordant results are often observed. Feline cases have been reported from endemic areas in Italy, France, Spain and Portugal, but four cases were also diagnosed in Switzerland in cats that had travelled to or been imported from Spain. Half of the cases were diagnosed in cats with impaired immune responses. Clinical manifestations compatible with feline leishmaniosis include lymph node enlargement, skin and mucocutaneous lesions, ocular lesions, chronic gingivostomatitis, hypergammaglobulinemia, and normocytic normochromic anemia. Cats have been empirically treated with some drugs used in dogs. Due to polymorphic clinical picture and the insidious progressive course, leishmaniosis can persist for a long time before dogs or cats are brought to a veterinarian and so diagnosis can be delayed. Exotic or new Leishmania spp. have been reported in humans, animals and vectors in Europe. This changing situation requires attention in Europe for designing epidemiological studies and control measures. © 2014 Elsevier B.V. All rights reserved.

1. Introduction

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Leishmania spp. are the causative agents of human and animal infections in wide areas of the Americas, Asia, Africa and Europe, and are transmitted by the bite of phlebotomine sand flies belonging to the genera Phlebotomus (Old World) or Lutzomyia (New World). The leishmanioses

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are the third most important vector-borne human diseases after malaria and lymphatic filariosis, largely afflicting the world’s poorest populations with difficult access to medical care (WHO, 2010; Alvar et al., 2012). They are considered neglected tropical and subtropical diseases and manifest as a skin or mucosal lesions or in a visceral form which is the most lethal parasitic disease after malaria (WHO, 2010). Currently, the leishmanioses are also endemic in extensive areas of temperate regions. This is the case in Europe, where they are reported to be spreading, making them emerging vector-borne diseases (Dujardin et al., 2008; Dantas-Torres et al., 2012; Ready, 2014). Taxonomy, epidemiology, immunology and the clinical pattern of the leishmanioses are quite complex as are control strategies. In Europe, as in other developed countries, pet population has increased and changed in recent years. Cats outnumber dogs in the European Union, where they live in at least 70 million households. A wide range of “non-conventional” pet species, including small mammals (pocket pets) has achieved popularity because of their small size and less expensive husbandry requirements (FEDIAF, 2012). Dogs and cats currently have an enhanced social role and zooanthropology appoints them as “family animals” rather than “companion animals”, because of the importance of the human–pet–animal bond. This means that a growing number of pets receive a high level of health care and at the same time live more closely with humans and travel with the family members for holidays. These animals play a role in a constantly evolving “One Health” scenario of leishmanioses, involving humans, animals and the environment as outlined in this review. 2. “Exotic” Leishmania spp. in Europe and the Mediterranean basin Leishmania infantum, the agent of zoonotic visceral and also cutaneous leishmanioses, is the only Leishmania spp. reported in both the Old and New Worlds. In the Old World it is widespread from the Mediterranean basin to the Middle East, Central and Southwestern Asia, northwestern China and North Africa, being the main reported species in Europe (WHO, 2010). L. infantum is included in the L. donovani complex or taxonomic group together with L. donovani sensu stricto. The dog is traditionally considered the main reservoir for L. infantum in a zoonotic transmission cycle, while L. donovani, the agent of human Kala-azar in the Indian subcontinent and East Africa, is reported to have humans as the reservoir, with its transmission cycle therefore considered to be anthroponotic (WHO, 2010). Recent studies confirm that there is not a clear genetic distinction between the two species and this may have practical consequences in the molecular identification of parasites, first of all in geographic areas where their distribution overlaps, as is the case in the eastern Mediterranean region (El Baidouri et al., 2013). Canine infection by L. donovani s.s. has been confirmed in endemic areas (Dereure et al., 2000, 2003; Nawaratna et al., 2009; Sharma et al., 2009; Alam et al., 2013) and a dog was found to be co-infected with both L. infantum and L. donovani in Cyprus (Antoniou et al., 2008). This means that L. donovani s.s. poses a potential threat to pet dogs living or visiting Cyprus (Antoniou et al., 2009).

Moreover, a serious risk for the spread of this anthroponotic species may derive from movements of infected dogs from Cyprus to other areas of Europe where permissive sand fly vectors suspected for L. donovani s.s. transmission are found (Antoniou et al., 2008, 2009; Mazeris et al., 2010). L. tropica is at present found in Europe in the Ionian islands of Greece and in Crete (Christodoulou et al., 2012). This species causes a well-known human cutaneous disease (Oriental sore or Aleppo boil) and its transmission cycle is considered anthroponotic because human patients are infectious to sand flies (WHO, 2010). Nevertheless, sporadic case reports of cutaneous or systemic canine disease caused by L. tropica have been observed (Dereure et al., 1991; Guessous-Idrissi et al., 1997; Mohebali et al., 2005, 2011; Pratlong et al., 2009; Toz et al., 2013; Ntais et al., 2013, 2014; Baneth et al., 2014). L. tropica may therefore affect dogs living or travelling to those eastern Mediterranean islands and it may be introduced to other parts of Europe where its recognized vector (P. sergenti) is present (Ready, 2010; Maia et al., 2013a; Gaglio et al., 2014). L. major has also been isolated from dogs in endemic areas (Pratlong et al., 2009). This species is the predominant agent of a human cutaneous leishmaniosis type in the Old World widespread from West Africa to the Middle East and India. L. major has a zoonotic transmission cycle linked to a wide range of various species of rodents which act as primary reservoirs. The investigation of a newly emerged focus in northern Israel pointed out the risk of diffusion of L. major in southern Europe based on the widespread co-distribution of both a reservoir (Microtus guentheri) and the vector (P. papatasi) (Faiman et al., 2013). At the same time L. major DNA was found in Portugal in Sergentomyia minuta, a traditional vector of Sauroleishmania in lizards and in a tourist who had travelled in Croatia, reinforcing concerns about the spread of exotic Leishmania species in Europe (Posch et al., 2012; Campino et al., 2013). L. siamensis, a species of recent identification in human patients in Thailand, has also been sequenced from autochthonous infections in horses in Germany, Switzerland and Florida and from a bovine in Switzerland (Sukmee et al., 2008; Müller et al., 2009; Lobsiger et al., 2010; Suankratai et al., 2010; Bualert et al., 2012; Reuss et al., 2012). New fields of investigation are opening up on potentially new zoonotic Leishmania spp., which may also involve cats (Sukmee et al., 2008). Therefore epidemiological changes will require in Europe the use of typing methods capable of distinguishing different Leishmania spp. infecting or co-infecting a human or pet animal patient and so making a correct prognostic evaluation and treatment decision (Haralambous et al., 2008). Moreover, the same strategy is important in epidemiological studies and for designing appropriate control measures (Toz et al., 2013). 3. Dynamics of reservoirs and vectors of L. infantum in Europe L. infantum is the most important Leishmania spp. worldwide from both a veterinary and a public health point of view. The basic paradigm of the dog as the main reservoir sustained by the high prevalence of canine infection in

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endemic areas and the infectiousness of dogs to sand flies, restricted the role of other mammals (included humans) to that of secondary reservoirs or occasional hosts with limited epidemiological relevance (Baneth et al., 2008). This was the case of a long list of wild carnivores (red fox (Vulpes vulpes), wolf (Canis lupus), badger (Meles meles), pine marten (Martes martes), stone marten (Martes foina), pole cat (Mustela putorius), mink (Mustela lutreola), genet (Genetta genetta), wild cats (Felis silvestris silvestris), and Iberian lynx (Lynx pardinus)) or synanthropic rodents (house mouse (Mus musculus), rat (Rattus spp.)) that were found infected in Europe (Sobrino et al., 2008; Helhazar et al., 2013; Del Rio et al., 2014; Millán et al., 2014;). This theory is now undermined by recent data concerning the role of infected healthy people and other animal species – such as cats and lagomorphs – as possible reservoirs of the infection (Maroli et al., 2007; Dujardin et al., 2008; Scarlata et al., 2008; Biglino et al., 2010; Molina et al., 2012; Poeppl et al., 2013; Díaz-Sáez et al., 2014; Jiménez et al., 2014; Moreno et al., 2014a). A epidemic outbreak of human visceral leishmaniosis began in 2010 in the periphery of Madrid after the establishment of a periurban green park in which a large population of hares (Lepus granatensis) grew up (Molina et al., 2012). Thirty per cent of the hares were found to be infected and were confirmed as reservoirs by means of xenodiagnosis and entomological studies on the feeding preference of the vector (Molina et al., 2012; Jimenéz et al., 2013). Conversely, in the same area, the percentage of dogs with specific antibodies was low (1.64%) and 7.3% of cats and 1.5% of rabbits were found to be PCR positive (Antoniou et al., 2013). Sand flies remain the sole proven vector, with a central role in the epidemiology of leishmaniosis in endemic areas and insect saliva components have an important role in the pathogenesis of leishmaniosis (Maroli et al., 2013). The non-vectorial transmission may occur in humans and dogs by means of blood product transfusion (Bruce-Chwatt, 1972; de Freitas et al., 2006; Tabar et al., 2008) and by venereal or vertical routes (Symmers, 1960; Eltoum et al., 1992; Masucci et al., 2003; Turchetti et al., 2014). Nonvectorial transmission has probably minor epidemiological relevance in endemic areas but this mode of transmission has to be considered by practitioners and breeders managing infected dogs. Moreover it has a primary role in areas where the vector is absent (Solano-Gallego et al., 2011). Indeed vertical transmission has probably had a major role in the outbreak of canine leishmaniosis (CanL) in North America (Boggiatto et al., 2011). Exchange of infected needles among HIV+ drug users is also a proven way of transmission in humans (Alvar et al., 2008). Information on the presence of sand flies with recognized vectorial capacity regarding CanL in Europe are available mainly from endemic areas and it varies according to collection site and technique (Rossi et al., 2008; Dantas-Torres et al., 2014; Gaglio et al., 2014). Detailed information for individual countries are reported in Table 1. P. perniciosus, P. ariasi, P. perfiliewi, P. neglectus, P. papatasi, P. sergenti, P. similis, P. kandelaki, P. balcanicus, P. langeroni and P. tobbi are the Leishmania vectors found in Europe (Maroli et al., 2013; Mencke, 2013; Antoniou et al., 2013; Medlock et al., 2014). P. mascittii is strongly suspected to be involved

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in transmission in some non-endemic areas in Germany, Belgium, France and Austria, and it has reached the 50◦ N latitude in Europe in the Rhinenland-Palatinate, on the Mosel river, which is the northernmost finding of a sand fly species in Europe (Naucke et al., 2008). Even P. perniciosus, P. neglectus and P. ariasi have expanded their distribution in some non-endemic areas in Germany, France and northern Italy (Maroli et al., 2008; Naucke et al., 2008; Dereure et al., 2009). Further ecoepidemiologic studies will probably confirm the occurrence of sand fly vectors in regions where appropriate bioclimatic characteristics exist (Dereure et al., 2009). Moreover, as climate is expected to change rapidly in the 21st century, a biogeographic evaluation of Central Europe coupled to the most likely routes of natural dispersal for the main sand fly vectors was recently made. The results led to the hypothesis that, by the second half of the century, climate in that area will be suitable for vector species with a current southwestern distribution (P. ariasi, P. mascittii and P. perniciosus) (Fisher et al., 2011). At the same time, under laboratory conditions many sand fly species supported the development of various Leishmania spp. compared to others which are considered “specific vectors” as they support the replication of one Leishmania spp. only (P. papatasi of L. major, P. sergenti of L. tropica) (Volf and Myskova, 2007). This permissive behavior may obviously have important epidemiological consequences concerning the circulation of “exotic” Leishmania spp. in Europe. In sum, reservoirs and vectors are the key points for the control of leishmaniosis in Europe, but a One Health approach is needed for intervention strategies because of the strong link between environment, animals and humans (Day, 2011). 4. Canine leishmaniosis in Europe Canine L. infantum infection has a great importance in Europe from both a public health and veterinary point of view. On the public health side, the dog is univocally recognized as the main reservoir for L. infantum and it has been estimated that at least 2.5 million dogs are infected in southwestern Europe (Moreno and Alvar, 2002; Athanasiou et al., 2012). However, in endemic areas of Europe CanL is focally distributed with a high variability in the prevalence of infection between hypoendemic and hyperendemic foci. An epidemiological study combining molecular, serological and delayed-type hypersensitivity (DTH) testing with leishmanin antigen, found a prevalence rate of 84.5% in Sicily (Lombardo et al., 2012). Moreover, a longitudinal study performed in south Italy showed that in a group of naïve dogs introduced in a hyperendemic focus, all individuals become infected after three transmission seasons (Oliva et al., 2006). In the face of very high levels of infection, clinical disease affects only a limited proportion of infected dogs, representing the tip of the iceberg in an endemic area (Fig. 1). A more consistent number of dogs has specific antibodies but no clinical signs (Fig. 1). A third and more numerous group of dogs is formed by healthy, antibody negative, PCR positive dogs (Baneth et al., 2008). According to longitudinal studies, healthy PCR and antibody positive dogs living in endemic areas usually develop clinical signs in the short or medium term (Foglia Manzillo

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Reference

P. similis, P. alexandi, P. neglectus/syriacus, P. perfiliewi, P. tobbi, P. papatasi, P. sergenti, P. mascittii P. perfiliewi, P. tobbi, P. neglectus/syriacus, P. similis, P. papatasi, P. alexandri, P. simici, P. mascittii, P. adlerius,P. balcanicus, P.syriacus, P. sergenti, Sergentomyia spp. P. perfiliewi, P. tobbi, P. neglectus/syriacus, P. mascittii, P. papatasi, P. sergenti, P. perniciosus,S. minuta P. neglectus, P. perfiliewi, P. tobbi, P. papatasi P. perfiliewi, P. tobbi, P. neglectus/syriacus, P. papatasi, P. sergenti P. neglectus/syriacus, P. perfiliewi, P. tobbi, P. papatasi, P. sergenti P. perfiliewi, P. similis, P. tobbi, P. neglectus, P. papatasi P. neglectus/syriacus, P. perfiliewi, P. papatasi, P. mascittii P. perfiliewi, P. neglectus/syriacus, P. papatasi, P. sergenti P. papatasi, P. sergenti, P. perniciosus, P. perfiliewi, P. balcanicus, P. tobbi, P. perfiliewi, P. neglectus/syriacus, P. tobbi, P. papatasi, P. sergenti P. neglectus/syriacus, P. perfiliewi, P. papatasi

Alten (2012)

P. mascittii P. mascittii, P. perniciosus

Horse Dog Dog Cat, Horse and Bovine Dog

Switzerland

Sand flies

P. mascittii P. perniciosus P. mascittii Black rat, Norwegian rat, house mouse, fox, wolf

P. perniciosus, P. perfiliewi, P. ariasi, P. mascittii, P. neglectu/syriacus, P. papatasi, P. sergenti, S. minuta

Fox,

P. ariasi, P. perniciosus, P. perfiliewi,P. papatasi,P. sergenti, P. mascittii

Badger, fox, stone marten, genet, pine marten, wild cat, pole cat, mink, wolf, Iberian lynx, rabbits, hares

P. perniciosus, P. sergenti, P. ariasi, S. minuta, P. langeroni, P. papatasi, P. mascittii

Fox, wolf, Norwegian rat, house mouse

P. perniciosus, P. ariasi, P. papatasi, P. sergenti, S. minuta P. perfiliewi, P. perniciosus

Xanthopoulou et al. (2011) Ntais et al. (2013), Maroli et al. (2013), Millán et al. (2014), Chatzis et al. (2014) ´ Zivicnjak et al. (2005), Bosnic´ et al. (2006) Beck et al. (2008) Alten (2012) Alten (2012), Maroli et al. (2013), Bourdeau et al. (2014) Ivovic´ et al. (2003, 2004), Alten (2012) Alten (2012) Velo et al. (2003, 2005), Alten (2012) Farkas et al. (2011), Alten (2012) Alten (2012), Mircean et al. (2014) Alten (2012), Harizanov et al. (2013) Alten (2012) Alten (2012), Maroli et al. (2013), Shaw et al. (2009) Depaquit et al. (2005) ˜ Díaz-Espineira and Slappendel (1997) Moritz and Steuber (1999), Naucke and Pesson (2000), Naucke and Schmitt (2004) Müller et al. (2009) Leschnik et al. (2008) Naucke et al. (2011), Poeppl et al. (2013) Knechtli and Jenni (1989) Schawalder (1977), Rüfenacht et al. (2005), Müller et al. (2009), Lobsiger et al. (2010), Alten (2012), Richter et al. (2014) D’Urso et al. (2004), Rossi et al. (2008), Morosetti et al. (2009), Pennisi (2013), Signorini et al. (2013), Dantas-Torres et al. (2014), Gaglio et al. (2014), Millán et al. (2014) Dereure et al. (2009), Depaquit et al. (2010), Alten (2012), Dedet et al. (2013) Lachaud et al. (2013), Pennisi (2013), Millán et al. (2014) ˜ Criado-Fornelio et al. (2000), Navarro et al. (2010), Ortunez et al. (2010), Millán et al. (2011), Alten (2012), Molina et al. (2012); Alcover et al. (2013), Durán-Martínez et al. (2013), Ruiz-Fons et al. (2013), Del Rio et al. (2014), Díaz-Sáez et al. (2014), Mártin-Mártin et al. (2014), Millán et al. (2014) Dalmau et al. (2008), Sanches et al. (2011), Alten (2012), Branco et al. (2013), Millán et al. (2014) Maroli et al. (2013)

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Please cite this article in press as: Pennisi, M.G., Leishmaniosis of companion animals in Europe: An update. Vet. Parasitol. (2014), http://dx.doi.org/10.1016/j.vetpar.2014.12.023

Table 1 Leishmania spp. animal hosts or reservoirs and sandflies species reported in European countries. In some cases infection was demonstrated in the host by molecular or serological methods only. Scientific names of wild species are detailed in the text. A sand fly species is suspected to be a vector on the basis of WHO criteria (WHO, 2010) or on the basis of epidemiological evidence. L. infantum vectors: P. perniciosus, P. ariasi, P. perfiliewi, P. tobbi, P. negelectus; L. tropica vectors: P. similis, P. sergenti; L. major vector: P. papatasi.

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Fig. 2. Canine leishmaniosis: solitary firm, mild scaling papule beside the nostril (courtesy of M.G. Pennisi).

Fig. 1. Diagram representing a canine population exposed to infection in a L. infantum endemic area (modified from Baneth et al., 2008). Clinical disease affects only a small proportion of infected dogs, representing the tip of the iceberg. A more consistent number of dogs has specific antibodies and positive PCR, culture, DTH (Delayed-type hypersensitivity) test but no clinical signs. A third and more numerous group of dogs is formed by healthy, antibody and culture negative, PCR and DTH positive dogs. DTH may figure positive also in healthy dogs negative at serological and molecular tests. According to longitudinal studies, healthy PCR and antibody positive dogs living in endemic areas usually develop clinical signs in the short or medium term (Foglia Manzillo et al., 2013). A dog may change category during his life according to immune response and/or parasite challenge exposure: red arrows indicate a progression towards clinical disease and blue arrows represent a more efficient control of infection by the immune system.

et al., 2013). Lastly, a dog may change category during his life according to immune response and/or parasite challenge exposure and move towards the top of the “pyramid” or vice versa (Fig. 1). These mechanisms explain the wide range of incubation period of canine leishmaniosis which can vary between months to years. Dogs belonging to the more consistent group of PCR positive antibody negative individuals control the infection and behave as healthy carriers. The healthy carriers however contribute to infection of sand flies, sometimes to a lesser extent than the dogs positioned at upper levels of the pyramid (i.e. dogs with antibodies and dogs with clinical signs) (Baneth et al., 2008; Laurenti et al., 2013). A complex genetic background is strongly suspected to influence susceptibility or resistance of dogs to CanL. Epidemiological studies, candidate gene studies and a genome-wide approach were performed with this goal. Some breeds, such as the Boxer, have been reported to display a higher prevalence of clinical disease in some endemic areas, and the Ibizan hound has been found more resistant in Mallorca (Solano-Gallego et al., 2000; Baneth et al., 2008). Well studied immunological factors contribute to the different fates of infected dogs: innate and acquired immune response is

Fig. 3. Canine leishmaniosis: ulcerative dermatitis at the inner surface of the pinna (courtesy of M.G. Pennisi).

protective when a balanced T-cell mediated and humoral immunity develop, while progression to disease is associated with reduced T-cell mediated immunity and a marked humoral response (Baneth et al., 2008). A high degree of apoptosis in T-cell with loss of antigen-specific proliferation, IFN production and reactive oxygen intermediate production in infected macrophages are found in symptomatic dogs (Esch et al., 2013). Anti-Leishmania antibodies are not protective and are responsible for hyperglobulinemia and immune complex-mediated lesions in organs such as the kidney and eye (Baneth et al., 2008). An inflammatory response and oxidative stress is manifested in dogs developing clinical signs (Martínez-Subiela et al., 2002, 2014; Heidarpour et al., 2012; Almeida et al., 2013; Paltrinieri, 2013; Silvestrini et al., 2013; Souza et al., 2014). Even in the case of dogs developing clinical signs a marked variation in severity is found in the course of disease: from a mild and possibly self-limiting form, characterized by a solitary papular lesion (Fig. 2) or enlarged lymph node, to severe disease with diffuse exfoliative or ulcerative dermatitis, cachexia and renal disease leading to chronic renal failure (Figs. 3 and 4) (Baneth et al., 2008; Solano-Gallego et al., 2011; Lombardo et al., 2014). Apart from lymphoid organs, bone marrow, skin and mucous membranes, damage caused by the parasite has also been reported in natural or experimental infection in the thyroid, adrenal glands, myocardium, smooth and striate muscles, bone, joints, lungs, liver, tongue, oesophagus, stomach, gut, testicles, prostate, placenta, eyes, spinal nerves, spinal cord and brain (Ferrer et al., 1988; Oliveira et al., 1993; Cortese

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Fig. 4. Canine leishmaniosis: scaly dermatitis, blepharoconjunctivitis, atrophy of masseter and temporalis muscles (courtesy of M.G. Pennisi).

et al., 1999; Vamvakidis et al., 2000; Blavier et al., 2001; Agut et al., 2003; Diniz et al., 2005; Paciello et al., 2009; Alves et al., 2010; Naranjo et al., 2010; Boggiatto et al., 2011; Pinto et al., 2011; Mir et al., 2012; Silvestrini et al., 2012; Viegas et al., 2012; Marquez et al., 2013; Sakamoto et al., 2013; Figueiredo et al., 2014; José-López et al., 2014; Momo et al., 2014; Rosa et al., 2014; Sbrana et al., 2014; Silva et al., 2014). Potentially, any organ and tissue can be affected by the parasite or the immune-mediated reaction of the host, and the growing list of unusual presentations suggests that CanL can be included in the list of “the great imitators” that may present a challenge to veterinarians in their clinical practice. There is a wide range of serological and parasitological diagnostic tools available for CanL, whose cost-effective use depends on a reasoned approach. In dogs with suspected CanL, quantitative serology is confirmatory in case of high titers and is needed for the clinical staging of the disease and for the post therapy follow-up (Solano-Gallego et al., 2011). In fact, a significant increase of the antibody titer (more than two-fold dilutions) usually precedes clinical recurrences (Solano-Gallego et al., 2011). Rapid in-clinic serological tests are commercially available but they may provide discrepant results compared to quantitative tests mainly because of a lower sensitivity (Athanasiou et al., 2014; Solano-Gallego et al., 2014). The vaccination of dogs with the LiESP/QA-21 antiLeishmania vaccine, on sale in Europe, induces antibodies detectable by the immunofluorescence antibody test (IFAT). Suspected clinical leishmaniosis in vaccinated dogs requires the use of parasitological methods. A rapid antikinesin qualitative test claims to discriminate between antibodies induced by natural infection and those due to vaccination (Sagols et al., 2013). LiESP/QA-21 vaccinated dogs have also a positive DTH response to leishmanin (Papierok et al., 2013). Vaccine history is therefore crucial for interpreting results of Leishmania immunological tests in dogs in Europe. Negative serological tests in healthy dogs should be interpreted with caution, because infection cannot be ruled out. For this reason, in endemic areas blood from antibody negative donors may be infected (Tabar et al., 2008).

Ideally, each blood bag should be PCR-tested. A real time PCR by means of sensitive non-invasive sampling (bilateral conjunctival swab) should be obtained once or twice a year at the same time of serological testing of blood donors (Solano-Gallego et al., 2011; Lombardo et al., 2012). Apart from testing blood donors, efforts should be made to reduce the transfusional risk by means of adequate preventative measure regularly applied to candidate donors. CanL has been increasingly found in northern latitudes where sand flies are not found or have very low densities, such as The Netherlands, Germany, Hungary and central France as a consequence of dogs travelling to or rehoming of stray dogs from endemic areas (Tánczos et al., 2012; Ready, 2010). These dogs should also be PCR-tested to detect possible infection, because seroconversion may not occur in healthy carriers (Martinez et al., 2011; Foglia Manzillo et al., 2013; Geisweid et al., 2013). In any case, seroconversion occurs weeks to months after exposure, so it is advisable to postpone serological investigations a few months after a holiday in endemic area, unless there are clinical indications (Solano-Gallego et al., 2011). Despite the fact that new drugs have been licensed and new protocols investigated, no significant progress has been obtained in the last 30 years for the therapy of CanL and the clinical response to treatment of sick dogs is variable. Clinical cure is often obtained associated with a reduction in parasite load and infectiousness, but clinical recurrence might occur and an appropriate life-long posttherapy follow-up should be maintained (Solano-Gallego et al., 2011). Meglumine antimoniate, miltefosine and paromomycin sulfate are the drugs which are licenced for the treatment of CanL in Europe. Paromomycin has a low therapeutic index and causes nephrotoxicity and otovestibular toxicity (Oliva et al., 1998). In a One Health approach, dogs should not be treated with drugs currently used in humans, such as amphotericyn B, miltefosine and paromomycin, because of the recognized risk of drug resistance (Croft et al., 2006; Dujardin et al., 2008; Maia et al., 2013b). The most frequently used protocol in dogs is the association of meglumine antimoniate for 1–2 months and allopurinol, until clinical and parasitological follow-up suggest discontinuation (Miró et al., 2008). Allopurinol can be given alone in mild cases and it is probably the most frequently used drug in Europe (Solano-Gallego et al., 2011; Bourdeau et al., 2014). Chronic kidney disease is the major prognostic factor in CanL and treatment is able to reduce the renal damage and allow a longer survival time (Plevraki et al., 2006; SolanoGallego et al., 2011; Geisweid et al., 2012; Pierantozzi et al., 2013; Goldstein et al., 2013). Prevention strategies against leishmaniosis find the best tools in the individual use of synthetic pyrethroids on dogs. They are available as spray, spot-on or collar formulations with different timings of onset and duration of activity, which has to be complied with throughout the whole exposure period to sand fly bites of dogs living in or travelling to endemic areas (Solano-Gallego et al., 2011). In field trials, protection with these products ranges from 50 to 100% along two transmission seasons and their large-scale use can have a significant impact at the population level (Otranto and Dantas-Torres, 2013; Brianti et al., 2014).

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Specific anti-Leishmania and anti-vectorial treatment of dogs with confirmed CanL has a significant prophylactic impact at population level because it prevents transmission to sand flies. Reduced incidence of leishmaniosis was obtained when sheltered dogs were regularly treated with a comprehensive strategy including therapy of affected dogs and massive use of anti-vectorial devices (Podaliri Vulpiani et al., 2009). The most recent preventative measures available for CanL are targeted to the dog specific (vaccination) or non-specific (immune-modulation) immunity against Leishmania. Three different vaccines licensed for use in dogs are now available in Brazil (two products) and Europe (a different one). Data obtained with the oldest of these products in Brazil suggest that a reduction in incidence of human and canine infection can be obtained by vaccinating dogs (Otranto and Dantas-Torres, 2013). Protection against active infection and disease progression is the main goal of the LiESP/QA-21 anti-Leishmania vaccine on the market in Europe, where vaccination is currently added to individual protection with pyrethroids as part of an integrated approach of prevention strategies against leishmaniosis (Solano-Gallego et al., 2011). This vaccine is restricted to seronegative dogs aged more than 6 months and induces anti-Leishmania antibodies detectable by IFAT (Sagols et al., 2013; Martin et al., 2014; Moreno et al., 2014b). Domperidone, a hyperprolactinemic immunomodulatory drug, has recently been licensed in Europe for preventive and therapeutic use against CanL (GómezOchoa et al., 2009). This drug enhances innate defense mechanisms activating phagocytic cells and it has been found that a 30-day course of therapy has an early stimulatory effect which persists for 1 month after the end of administration, reducing the risk of developing CanL in case of infection (Gòmez-Ochoa et al., 2012). According to a recent controlled randomized clinical trial the quarterly administration of domperidone for 30 days reduces the risk of developing a clinical disease associated to Leishmania infection in dogs (Sabaté et al., 2014). Effective prevention measures require political choices for the economic impact of actions at a population or environmental level, which should be supported by current best practices for the control of the disease. The management of stray dogs and municipal kennels in some endemic areas in southern Europe should be a main concern for veterinary and public health authorities. Effective preventive and therapeutic measures are urgently needed for a high number of infected life-long sheltered dogs in public kennels in the absence of an acceptable level of health care. 5. L. infantum infection in other companion animals in Europe Cats outnumber dogs in Europe and are receiving a higher standard of medical care than in the past, as demonstrated by the existence of all-cat veterinary clinics and the rise of specialized practitioner associations, journals and boards of experts (European Advisory Board on Cat Diseases). In the past, cats were considered an accidental host for Leishmania spp. infection because of the sporadic case reports from endemic areas since the beginning of

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the 20th century (Pennisi, 2002, 2013). After the 1980s as the number of pet cats and their level of health care increased, case reports of feline leishmaniosis (FeL) have risen. In Europe, L. infantum is currently the only recognized Leishmania spp. isolated from cats (Ozon et al., 1998; Gramiccia et al., 2005; Grevot et al., 2005; Maroli et al., 2007; Pocholle et al., 2012). In a few feline cases an isoenzymatic characterization has reported MON1 as the most common zymodeme in cats, such as in dogs and humans (Ozon et al., 1998; Gramiccia et al., 2005; Maroli et al., 2007; Pocholle et al., 2012). In two cases from Sicily, MON72 and MON201 were isolated (Gramiccia et al., 2005). Restriction fragment length polymorphism investigations have confirmed that there is no genetic or phenotypic difference between strains isolated from cats or dogs (Millán et al., 2011). Blood meal analysis has confirmed that competent vector sand flies naturally fed on cats and xenodiagnosis substantiated that P. perniciosus in the Old World and L. longipalpis in the New World were infected with L. infantum after feeding on a naturally infected cat (De Colmenares et al., 1995; Maroli et al., 2007; da Silva et al., 2010; Afonso et al., 2012). Cats are therefore confirmed to have a role in the transmission cycle of L. infantum whose relevance has yet to be better defined. On the basis of many epidemiological studies performed by serological and/or molecular techniques, we know that feline infection may be frequent in endemic areas but prevalence is generally lower than that found in dogs in the same areas (Diakou et al., 2009; Maia et al., 2010; Millán et al., 2011; Chatzis et al., 2014; Miró et al., 2014). Antibody prevalence in cats has been found to range between 0 and 68.5%, and blood PCR prevalence between 0 and 60.6% (Pennisi, 2013). This variability may be due to different levels of endemicity, type of feline populations studied or different methodologies. With regard to this latter factor, we have to stress that validation of Leishmania diagnostic tests in cats is still lacking and a comparison of results from these different studies is not feasible because of extreme variations in the methodologies employed. For instance, the most widely used serological technique is IFAT but the applied cut-off ranges from 1:2 to 1:100. The cut-off level has, of course, a dramatic effect on the estimated prevalence and it is also well known that when low serum dilutions are used cross-reactions cannot be ruled out. According to the results obtained from cats with infection confirmed by isolation (positive controls) and from feline serum samples obtained from non-endemic areas (negative controls), 1:80 is the dilution proposed as a cut-off for testing feline sera by IFAT, but more extensive studies are needed to confirm this finding (Pennisi et al., 2012). A molecular investigation was done for the first time on lymph node and conjunctival swab samples, obtaining in South Italy positivity of 11.7% and 16.7%, respectively, compared to 7.8% from blood in EDTA (Pennisi et al., 2012). More recently in Greece PCR positivity in different tissues from cats ranged from 3.1% (conjunctival swab) and 18.2% (skin biopsy) with a significantly higher prevalence rate in skin or bone marrow (16%) (Chatzis et al., 2014). When epidemiological studies tested cats by both serological and molecular techniques, the two methodologies provided discordant results (Pennisi et al., 2000;

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Fig. 6. Feline leishmaniosis: hemorrhagic nodul on the head (courtesy of M.G. Pennisi).

Fig. 5. Feline leishmaniosis: ulcerative dermatitis on distal limb (courtesy of M.G. Pennisi).

Martin-Sanchez et al., 2007; Ayllon et al., 2008; Maia et al., 2010; Millán et al., 2011; Sherry et al., 2011; Pennisi et al., 2012; Sobrinho et al., 2012). In dogs a positive PCR in the lack of serological evidence of infection is found in “resistant” individuals reacting towards the pathogen with a cell-mediated response alone or in the case of early infection (Foglia Manzillo et al., 2013). Based on a few longitudinal studies, in general blood PCR is repeatedly found positive when cats are tested several times and IFAT titer does not change significantly for months or years as it typically occurs in dogs with subclinical infections (Pennisi et al., 2000; Vita et al., 2005; Maroli et al., 2007; MartinSanchez et al., 2007). Between 1977 and 2014 a total of 46 clinical cases and 15 histological descriptions have been published in which leishmaniosis was confirmed in cats in Europe by serological and/or parasitological methods (Dalmau et al., 2008; ˜ Navarro et al., 2010; Ortunez et al., 2010; Sanches et al., 2011; Pennisi, 2013; Richter et al., 2014). The European feline cases were reported from endemic countries, i.e. Italy (27 cases), Spain (21 cases), France (6 cases) and Portugal (3 cases), but it is noteworthy that four cases were diagnosed in Switzerland in cats that had travelled to or had been imported from Spain (Schawalder, 1977; Rüfenacht et al., 2005; Richter et al., 2014). The disease has been reported in adult cats (age range: 2–15 years) and in half of them an impaired immune response was found, due to concomitant retroviral infection (Feline Immunodeficiency Virus (FIV) or both Feline Leukemia Virus and FIV) or immune-suppressive therapy. On the basis of information derived from these reports, signs and clinicopathological abnormalities compatible with FeL include lymph node enlargement and skin lesions, such as ulcerative, crusty or nodular dermatitis (mainly on the head or distal limbs), ocular lesions (mainly uveitis), chronic gingivostomatitis or mucosal nodules, muco-cutaneous ulcerative or nodular lesions, hypergammaglobulinemia and normocytic normochromic anemia (Figs. 5 and 6). However, it must be pointed out that some cases were diagnosed in cats with chronic renal failure or with unusual clinical presentations, such as fever, jaundice, malabsorption or pancytopenia. Antibody detection has been the most commonly used

diagnostic technique, but in rare cases a low IFAT titer (<80) was found, so parasitological tests should also be run in suspected cases with doubtful serology (Pennisi, unpublished data). In fact, cytological, histological, molecular or cultural investigations performed on affected tissues (mainly skin, lymph nodes, oral tissue samples, enucleated ocular globes and nasal discharge) and also blood, buffy coat and bone marrow samples can contribute to confirm a diagnosis of FeL (Pennisi, 2013). Long-term oral therapy with allopurinol or subcutaneous injections of meglumine antimoniate have been used for treating cats, but we do not currently have any pharmacokinetic or pharmacodynamic information on their use in cats. They were usually well tolerated but a careful monitoring of renal and liver functions is advisable during allopurinol therapy, because of the rare occurrence of increased ALT (alanine aminotransferase) and AST (aspartate aminotransferase) value or signs of acute kidney injury (Rüfenacht et al., 2005; Pennisi, unpublished data). Prognosis varies in cats from good to poor according to many factors, as in dogs. The development of chronic renal failure is reported in both treated and untreated cats, and glomerular disease should be investigated because of the frequent occurrence of hyperglobulinemia and the consequent risk for immunecomplex-related renal disease (Pennisi et al., 2004; Pennisi, unpublished data). In the long list of the most common non-conventional house pets we find some species which are susceptible to L. infantum: i.e. the ferret, gerbil, hamster, guinea pig, mouse and rat. According to recent studies on leishmaniosis in sylvatic lagomorphs, pet rabbits should also be included in the above list (Díaz-Sáez et al., 2014; Martín-Martín et al., 2014; Moreno et al., 2014a). To the best of our knowledge, the natural disease has never been reported in animal pets belonging to these species in Europe with the exclusion of a case report in a pet ferret in Sicily, in which the diagnosis was confirmed by PCR from blood, skin and bone marrow (Brianti et al., 2005). The 6-year-old male ferret was affected with lymph node enlargement and dermatitis which spontaneously resolved in a few months. Feline practitioners and those taking care of other pet species in endemic areas should be aware of their susceptibility to Leishmania infection. Moreover, in non-endemic areas, history on any new feline or other pet patient should always include information on the geographic origin and movements.

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6. Conclusion Leishmaniosis is one of the canine diseases most feared by veterinary practitioners and dog owners living in European endemic areas because of the dog life risk and impact on welfare. CanL also has a direct and indirect strong economic impact not only in case of clinically affected animals (cost of diagnostics, therapy, long-life follow up, etc.) but also for periodical screening and preventative measures (repellent devices, vaccination, etc.) in dogs at risk of infection. Because of the susceptibility of cats to infection and their risk of developing a severe chronic disease, FeL should not be neglected. Due to the polymorphic clinical picture and the insidious progressive course of the disease, leishmaniosis could persist for long time before dogs or cats are brought to a veterinarian and diagnosis can be delayed mostly in non-endemic areas. Leishmaniosis should also be taken into account also in non-conventional companion animals, such as carnivores, rodents and lagomorphs, which are potentially susceptible to the disease. In conclusion, the importance of leishmaniosis in Europe is growing because of many environmental, animal and human factors: (i) bioclimate changes support the increase and spread of sand fly vectors; (ii) environmental changes sustain the numerical increase of populations of “new” wild reservoir species; (iii) increasing numbers of “family animals” regularly move with people for holidays to endemic areas or they are re-homed from these areas to non-endemic ones; (iv) large populations of stray dogs and cats and sheltered animals do not receive adequate health control in some endemic areas; (v) no sterile cure is possible for infected dogs and possibly for infected cats; (vi) “exotic” Leishmania spp. are entering Europe, where they can spread. An increasing number of companion animals and humans is therefore expected to be at risk regarding the leishmanioses and this is a big challenge that requires a global “One Health” approach. Conflict of interest I wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. References Afonso, M.M., Duarte, R., Miranda, J.C., Caranha, L., Rangel, E.F., 2012. Studies on the feeding habits of Lutzomyia (Lutzomyia) longipalpis (Lutz & Neiva, 1912) (Diptera: Psychodidae: Phlebotominae) populations from endemic areas of American visceral leishmaniasis in Northeastern Brazil. J. Trop. Med., http://dx.doi.org/10.1155/2012/858657 (ID 858657). Agut, A., Corzo, N., Murciano, J., Laredo, F.G., Soler, M., 2003. Clinical and radiographic study of bone and joint lesions in 26 dogs with leishmaniasis. Vet. Rec. 153, 648–652. Alam, M.Z., Yasin, G., Kato, H., Sakurai, T., Katakura, K., 2013. PCR-based detection of Leishmania donovani DNA in a stray dog from visceral leishmaniasis endemic focus in Bangladesh. J. Vet. Med. Sci. 75, 75–78. Alcover, M.M., Ballart, C., Serra, T., Castells, X., Scalone, A., Castillejo, S., Riera, C., Tebar, S., Gramiccia, M., Portús, M., Gállego, M., 2013. Temporal trends in canine leishmaniosis in the Balearic Islands (Spain): a veterinary questionnaire. Prospective canine leishmaniosis survey and entomological studies conducted on the Island of Minorca, 20 years after first data were obtained. Acta Trop. 128, 642–651.

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