key: cord-0948655-3ohcwtp9
authors: Pereira, André; Maia, Carla
title: Leishmania infection in cats and feline leishmaniosis: An updated review with a proposal of a diagnosis algorithm and prevention guidelines
date: 2021-06-02
journal: Curr Res Parasitol Vector Borne Dis
DOI: 10.1016/j.crpvbd.2021.100035
sha: 75e0c64cf9815a83b95265fdedc91a30794258af
doc_id: 948655
cord_uid: 3ohcwtp9

Leishmaniosis is a vector-borne disease caused by protozoans of the genus Leishmania, which are transmitted to vertebrates, including cats, through the bites of female phlebotomine sand flies. An increasing number of epidemiological and experimental studies concerning Leishmania infection in cats, as well as case reports of clinical leishmaniosis in these felids, have been published in recent years. In the present study, a comprehensive review was made by sourcing the National Library of Medicine resources to provide updated data on epidemiology, immunopathogenesis, diagnosis, treatment, and prevention of feline leishmaniosis. Cats were found infected with Leishmania parasites worldwide, and feline leishmaniosis appears as an emergent disease mostly reported in countries surrounding the Mediterranean Sea and in Brazil. Cats with impaired immunocompetence seem to have a higher risk to develop clinical disease. The main clinical and clinicopathological findings are dermatological lesions and hypergammaglobulinemia, respectively. Diagnosis of feline leishmaniosis remains a challenge for veterinarians, in part due to the lack of diagnosis support systems. For this reason, a diagnostic algorithm for clinical decision support is herein proposed. No evidence-based treatment protocols are currently available, and these remain empirically based. Control measures are limited and scarce. Thus, a set of prevention guidelines are herein suggested.

Leishmaniosis is a disease that affects humans and both domestic and wild animals worldwide and is caused by protozoans of the genus Leishmania. The infection typically occurs through the bites of female phlebotomine sand flies of the genera Phlebotomus in the Old World and Lutzomyia in the New World (WHO, 2010) .

In contrast to dogs, cats have been considered for several years as accidental hosts resistant to leishmaniosis. Nevertheless, this felid now appears as a relevant piece within the ecological system in which Leishmania parasites are maintained indefinitely (Asfaram et al., 2019) . Feline Leishmania infection has frequently been reported in endemic areas of South America, Southern Europe and Western Asia, and the number of reported cases of feline leishmaniosis has been increasing in recent years (Pereira et al., 2019b; Baneth et al., 2020; da Costa-Val et al., 2020; Fernandez-Gallego et al., 2020) .

The present review aimed to provide updated information concerning the epidemiology of Leishmania infection in cats and clinical management of feline leishmaniosis (FeL) with emphasis on immunopathogenesis, diagnosis, treatment, prognosis, and prevention, as well as the development of an algorithm to assist diagnosis and delineate strategic guidelines to prevent feline infection.

A comprehensive literature search was performed on 10 March 2021 by sourcing National Library of Medicine (NLM) resources through PubMed (https://pubmed.ncbi.nlm.nih.gov/) using the following Boolean string: ("leishmania" [MeSH Terms] OR "leishmania"[All Fields] OR "leishmanias" [All Fields] OR "leishmaniae" [All Fields] OR ("leishmaniasis" [MeSH Terms] OR "leishmaniasis" [All Fields] OR "leishmaniosis" [All Fields] OR "leishmaniases" [All Fields])) AND ("cat" [All Fields] OR ("felis" [MeSH Terms] OR "felis" [All Fields]) OR ("felidae" [MeSH Terms] OR "felidae" [All Fields] OR "felid" [All Fields] OR "felids" [All Fields]) OR ("cats" [MeSH Terms] OR "cats" [All Fields] OR "felines" [All Fields] OR "felidae" [MeSH Terms] OR "felidae" [All Fields] OR "feline" [All Fields])). Search results were saved as a comma-separated value (CSV) file, subsequently imported into Microsoft® Excel®. Study eligibility was manually assessed by two independent investigators in a blinded manner. Only available original (v) L. (L.) tropica in western Asia Can et al., 2016; Akhtardanesh et al., 2017) ; (vi) L. (L.) venezuelensis in Venezuela (Bonfante-Garrido et al., 1991) ; and (vii) L. (V.) braziliensis in Brazil da Costa-Val et al., 2020) and French Guiana (Rougeron et al., 2011) .

Besides, DNA of L. infantum and putative L. major/L. donovani (s.l.) hybrid parasites were detected in wild cats (Felis silvestris) in Spain (Del Río et al., 2014) and in a domestic cat in mainland Portugal , respectively.

The proportion of cats infected with or exposed to Leishmania has been assessed in several epidemiological studies through parasitological, serological, or molecular methods (Table 1 and Table 2 ). However, reported values vary greatly (from 0 to > 70%) and appear to be influenced by local endemicity, sampling bias and heterogeneity/performance of diagnostic methodologies (manly cut-off, target gene and sample used for testing).

Specific antibodies or Leishmania DNA have been mostly detected in domestic cats living in endemic areas of South America, the Mediterranean Region and western Asia. Some studies also suggest that wild cats from Spain (Del Río et al., 2014; Risueño et al., 2018) and sand cats (Felis margarita) from Saudi Arabia (Morsy et al., 1999 ) are frequently exposed to Leishmania infection.

In non-endemic countries, as seen in dogs, feline Leishmania infection has been particularly associated with cats travelling to or rehomed from southern Europe and Brazil (Rüfenacht et al., 2005; Richter et al., 2014; Maia & Cardoso, 2015; Sch€ afer et al., 2021) . Also, antibodies to Leishmania were detected in three domestic cats living in the UK, but in all cases, the travel and clinical history were unknown .

Although blood transfusion is regarded as a probable non-vectorborne transmission pathway of Leishmania in cats, no feline infection cases by this parasite (screened by PCR) were identified among eligible blood donors (Marenzoni et al., 2018; Mesa-Sanchez et al., 2020) .

Several factors have been highlighted as possibly associated with Leishmania infection in cats based on univariate analysis, including old age (Akhtardanesh et al., 2017; Junsiri et al., 2017; Morganti et al., 2019; Asgari et al., 2020) , male sex (Cardoso et al., 2010; Sobrinho et al., 2012; Montoya et al., 2018a; Asgari et al., 2020; Latrofa et al., 2020) , non-neutered status Latrofa et al., 2020) , presence of clinical or clinicopathological abnormalities (such as crusting skin lesions, leukopaenia, increase in alanine aminotransferase (ALT) levels, lymphadenomegaly, lymphocytosis and neutrophilia) Sherry et al., 2011; Sobrinho et al., 2012; Spada et al., 2013; Akhtardanesh et al., 2017; Otranto et al., 2017; Latrofa et al., 2020) , concomitant infections (such as feline coronavirus (FCoV), feline immunodeficiency virus (FIV), feline leukemia virus and Toxoplasma gondii) (Sherry et al., 2011; Sobrinho et al., 2012; Spada et al., 2013 Spada et al., , 2016 Montoya et al., 2018a) , geographical area/local environment (such as altitude and rural areas) (Nasereddin et al., 2008; Cardoso et al., 2010; Asgari et al., 2020) , lifestyle (such as access to the outdoors) and cohabitation with dogs Morelli et al., 2020) . Epidemiological studies using logistic regression models (a powerful analytic research tool that avoids confounding effects) have evidenced that adult cats Akhtardanesh et al., 2020) , males Akhtardanesh et al., 2020) , non-neutered , or with concomitant infections by FeLV (Martín-S anchez et al., 2007; Sherry et al., 2011; Spada et al., 2013; Akhtardanesh et al., 2020) , FIV Akhtardanesh et al., 2020) , "Candidatus Mycoplasma turicensis" or Hepatozoon spp. have an increased risk for Leishmania infection.

In dogs, several studies have provided evidence demonstrating that the course of L. infantum infection is directly linked to the immune response. Development of progressive disease in susceptible dogs is typically characterised by high antibody levels and an impaired ability to mount a strong and effective cell-mediated response characterised by the expression of interferon-gamma (IFN-γ), tumour necrosis factor-alpha (TNF-α), and interleukin (IL)-2 (reviewed by Maia & Campino, 2018) . However, very limited data are available on the pathogenesis of leishmaniosis in cats. Experimental studies involving intravenous/intraperitoneal inoculation of axenic promastigotes suggest that cats are hypothetically less susceptible to developing disease by L. infantum when compared to dogs, despite also presenting a long-lasting parasitaemia (Kirkpatrick et al., 1984; Akhtardanesh et al., 2018) . Recently, Priolo et al. (2019) demonstrated that cats naturally exposed to L. infantum infection produce IFN-γ following ex vivo blood stimulation with parasite antigens, as reported in dogs . This finding is important to highlight that Leishmania parasites can elicit a protective cell-mediated immune response in cats. The only study assessing the role of the complement system in feline L. infantum infection showed that, contrary to humans and dogs, catʼs proteins are consumed by parasites in the lectin pathway, which hypothetically may justify their low predisposition to develop clinical disease (Tirado et al., 2021) .

Feline leishmaniosis caused by L. infantum is mostly reported in adult (median age: 7 years; range: 2-21 years) domestic short-hair cats living in or travelling to endemic countries of southern Europe and Brazil. The disease has a chronic course and may be manifested by a plethora of clinical signs and/or clinicopathological abnormalities, which are summarised in Table 3 and Table 4 , respectively. About one-third of cats with leishmaniosis showed concomitant infections/diseases including FIV (Herv as et al., 2001; Poli et al., 2002; Pennisi et al., 2004; Grevot et al., 2005; Pocholle et al., 2012; Pimenta et al., 2015; Fernandez-Gallego et al., 2020) , FeLV (Poli et al., 2002; Grevot et al., 2005; Pereira et al., 2019c) , FCoV (Pennisi et al., 2004; Savani et al., 2004) , T. gondii (Pennisi et al., 2004) , Bartonella henselae (Pennisi et al., 2004) , diabetes mellitus (Leiva et al., 2005) , pemphigus foliaceus (Rüfenacht et al., 2005) , neoplasia (Grevot et al., 2005; Pocholle et al., 2012; Maia et al., 2015b) and/or were under immunosuppressive therapies at the time of diagnosis (Fernandez-Gallego et al., 2020) .

Dermatological disorders were found in about 75% of reported clinical cases. Although uncommon, they may occur in the apparent absence of other obvious signs of disease (Fernandez-Gallego et al., 2020) . Nodular dermatitis seems to be the main cutaneous lesion associated with FeL and is typically found on the eyelids (Herv as et al., 2001; Richter et al., 2014; Pimenta et al., 2015; Leal et al., 2018; Pereira et al., 2019c; Fernandez-Gallego et al., 2020; Silva et al., 2020) . Erosive/ulcerative dermatitis is another clinical finding suggestive of FeL and has been identified on the head (Herv as et al., 2001; Grevot et al., 2005; Coelho et al., 2010; Pocholle et al., 2012; Maia et al., 2015b; Basso et al., 2016; Brianti et al., 2019; Headley et al., 2019; Fernandez-Gallego et al., 2020) , extremities (Rüfenacht et al., 2005; Coelho et al., 2010; Basso et al., 2016; Fernandez-Gallego et al., 2020; Silva et al., 2020) , trunk Fernandez-Gallego et al., 2020) , and over bony prominences (Herv as et al., 1999) . Although less frequent, some cats with clinical leishmaniosis showed onychogryphosis (da Headley et al., 2019) , a rather specific sign of canine leishmaniosis (CanL) (Maia & Campino, 2018) . Generalised or focal lymphadenopathy appears as a common finding in FeL (Herv as et al., 1999; Poli et al., 2002; Savani et al., 2004; Pennisi et al., 2004; Maroli et al., 2007; da Silva et al., 2010; Brianti et al., 2019; Fernandez-Gallego et al., 2020; Silva et al., 2020) as well as non-specific signs including lethargy/depression (Poli et al., 2002; Pennisi et al., 2004; Leiva et al., 2005; Rüfenacht et al., 2005; Marcos et al., 2009; Pocholle et al., 2012; Richter et al., 2014; Fernandez-Gallego et al., 2020) , anorexia/inappetence (Pennisi et al., 2004; Rüfenacht et al., 2005; Marcos et al., 2009; da Silva et al., 2010; Fernandez-Gallego et al., 2020) , and weight loss Herv as et al., 1999; Pennisi et al., 2004; Savani et al., 2004; da Silva et al., 2010; Fernandez-Gallego et al., 2020; Silva et al., 2020) . Approximately one-fourth of cats with clinical leishmaniosis showed uveitis (Herv as et al., 2001; Pennisi et al., 2004; Verneuil, 2013; Richter et al., 2014; Pimenta et al., 2015; Leal et al., 2018; Pereira et al., 2019c; Fernandez-Gallego et al., 2020) ; stomatitis (Herv as et al., 2001; Leiva et al., 2005; Maroli et al., 2007; Verneuil, 2013; Maia et al., 2015b; Migliazzo et al., 2015; Fernandez-Gallego et al., 2020) and/or cardiorespiratory signs such as dyspnoea/tachypnoea, pallor, abnormal respiratory sounds, nasal discharge and sneezing (Herv as et al., 2001; Pennisi et al., 2004; Marcos et al., 2009; da Silva et al., 2010; Richter et al., 2014; Migliazzo et al., 2015; Maia et al., 2015b; Basso et al., 2016; Leal et al., 2018; Headley et al., 2019; Altuzarra et al., 2020; Silva et al., 2020) . Musculoskeletal (i.e. muscle atrophy; da , neurological (i.e. ataxia; Fernandez-Gallego et al., 2020) , and urogenital (i.e. vaginal bleeding; Maia et al., 2015b ) signs were also occasionally described, but in some cases, they appear to be secondary to concomitant diseases Fernandez-Gallego et al., 2020) . Other clinical manifestations rarely found and which may represent a further diagnostic challenge to veterinarians include: depigmentation (Rüfenacht et al., 2005; Pocholle et al., 2012) , cutaneous bloody cyst (Pennisi et al., 2004) , pruritus (Rüfenacht et al., 2005; Pocholle et al., 2012) , footpad hyperkeratosis (Fernandez-Gallego et al., 2020), hepatomegaly (Pennisi et al., 2004; Leiva et al., 2005) , splenomegaly (Poli et al., 2002; Leal et al., 2018) , bruising , mastitis , chorioretinitis (Pennisi et al., 2004; Fernandez-Gallego et al., 2020) , corneal opacification (Herv as et al., 2001; Pimenta et al., 2015) , glaucoma (Leiva et al., 2005; Richter et al., 2014) , blepharitis (Brianti et al., Most consistent laboratory abnormalities found in FeL cases include anaemia (generally of the normochromic, normocytic type) (Herv as et al., 1999; Pennisi et al., 2004; Marcos et al., 2009; Richter et al., 2014; Pimenta et al., 2015; Pereira et al., 2019c; Fernandez-Gallego et al., 2020) and hyperproteinaemia with hypergammaglobulinaemia Herv as et al., 1999; Poli et al., 2002; Pennisi et al., 2004; Leiva et al., 2005; Marcos et al., 2009; Richter et al., 2014; Basso et al., 2016; Leal et al., 2018; Brianti et al., 2019; Pereira et al., 2019c; Altuzarra et al., 2020; Fernandez-Gallego et al., 2020) . The latter was detected in more than 80% of sick cats and should be investigated as a possible biomarker of FeL. Leukocytosis da Silva et al., 2010; Fernandez-Gallego et al., 2020) and leukopaenia (Pennisi et al., 2004; Rüfenacht et al., 2005; Richter et al., 2014) are inconsistent findings, whereas thrombocytopenia (Pennisi et al., 2004; Marcos et al., 2009; Richter et al., 2014; Pimenta et al., 2015; Basso et al., 2016; Pereira et al., 2019c) and azotaemia (Pennisi et al., 2004; Leiva et al., 2005; Marcos et al., 2009; da Silva et al., 2010; Leal et al., 2018; Fernandez--Gallego et al., 2020) have been frequently reported. About a quarter of the sick cats presented proteinuria (Marcos et al., 2009; Leal et al., 2018; Fernandez-Gallego et al., 2020) , suggesting a possible association between FeL and kidney disease as described in dogs. Recently, Chatzis et al. (2020) observed that cats infected with Leishmania parasites had higher concentrations of inorganic phosphorus than non-infected cats, reinforcing this assumption. Mild increases of liver enzyme activities are also described (Fernandez-Gallego et al., 2020), but less frequently than in cases of CanL (Maia & Campino, 2018) .

Clinical presentation combined with epidemiological context may lead to suspicion of FeL, but for a definitive diagnosis, Leishmania-specific laboratory tests are required (Table 5 ). These include direct tests (cytology, histology, immunohistochemistry, culture, and PCR), demonstrating the presence of the parasite or its components, and indirect tests (serology) assessing the hostʼs response to infection.

Cytology is strongly advised in cats presenting erosive/ulcerative skin disease, nodular lesions and/or lymphadenomegaly (Herv as et al., 1999; Poli et al., 2002; Savani et al., 2004; Abbreviations: CAG, crude antigen; CH1, chitinase; cytB, cytochrome b; DAT, direct agglutination test; DB, dot blot; ELISA, enzyme-linked immunosorbent assay; EU, ELISA units; F., Felis; FML, fucose-mannose ligand; gp63, metalloprotease gp63; H, total parasite extract; IFAT, immunofluorescence antibody test; IHC, immunohistochemistry; ITS1, internal transcriber spacer 1; kDNA, kinetoplast minicircle DNA; L., Leishmania; na, not available; nPCR, nested PCR; PCR, one-step PCR (polymerase chain reaction); qPCR, real-time PCR; RFLP, restriction fragment length polymorphism; rK39, recombinant K39; SODe, superoxide dismutase excreted; SSU, small subunit ribosomal DNA; WB, western blot. . Nevertheless, compared with cytology, histology has the main advantage of providing a more detailed diagnostic information on the tissue architecture, which allows understanding if parasites are indeed associated with lesions (Paltrinieri et al., 2016) . Immunohistochemistry may be further performed to confirm the presence of Leishmania organisms in biological samples obtained from cats (Poli et al., 2002; Navarro et al., 2010; Migliazzo et al., 2015) . Based on histological and immunohistochemical examinations, it has been observed that this parasite may invade several feline organs/tissues such as skin Poli et al., 2002; Grevot et al., 2005; Rüfenacht et spleen (Herv as et al., 1999; Grevot et al., 2005; Marcos et al., 2009; Maia et al., 2015b; Fernandez-Gallego et al., 2020; Silva et al., 2020) , bone marrow Pimenta et al., 2015; Silva et al., 2020) , and lymph nodes (Herv as et al., 1999) , and may also be associated with neoplasia (Grevot et al., 2005; Rüfenacht et al., 2005; Pocholle et al., 2012; Maia et al., 2015b; Altuzarra et al., 2020) . Parasite culture is an accurate test allowing conclusive diagnosis of an active infection. However, this test is not suitable for rapid diagnosis and is restricted to specialised laboratories. Parasite culture is a starting point for parasite identification and characterisation by isoenzyme electrophoresis . Viable parasites have been isolated from whole blood , nodular lesions (Poli et al., 2002; Basso et al., 2016) , liver Silva et al., 2020) , spleen Silva et al., 2020) , lymph nodes (Pennisi et al., 2004; Maroli et al., 2007; Maia et al., 2015b; Basso et al., 2016; Silva et al., 2020) , and bone marrow of cats with leishmaniosis.

Polymerase chain reaction (PCR)-based tests have allowed the detection of Leishmania DNA in several feline samples, including whole blood (Marcos et al., 2009; Pocholle et al., 2012; Pimenta et al., 2015; Basso et al., 2016; Attipa et al., 2017a; Brianti et al., 2019; Fernandez-Gallego et al., 2020; Silva et al., 2020) , buffy coat , conjunctival and oral swabs (Migliazzo et al., 2015; Brianti et al., 2019; da Costa-Val et al., 2020) , hair (Urbani et al., 2020) , skin (Rüfenacht et al., 2005; da Silva et al., 2010; Richter et al., 2014; Maia et al., 2015b; Basso et al., 2016; Fernandez-Gallego et al., 2020; Silva et al., 2020) , nasal tissue (Leal et al., 2018) , liver Silva et al., 2020) , spleen (Savani et al., 2004; Coelho et al., 2010; da Silva et al., 2010; Maia et al., 2015b; Pimenta et al., 2015; Fernandez-Gallego et al., 2020; Silva et al., 2020) , kidneys (da , lymph nodes (Poli et al., 2002; Pennisi et al., 2004; Coelho et al., 2010; da Silva et al., 2010; Maia et al., 2015b; Migliazzo et al., 2015; Pimenta et al., 2015; Silva et al., 2020) , bone marrow (da Richter et al., 2014; Pimenta et al., 2015; Fernandez-Gallego et al., 2020; Silva et al., 2020) , and inflammatory breast fluid . Conventional PCR, nested PCR, and real-time PCR (qPCR) targeting kinetoplast minicircle DNA (kDNA) or the small subunit ribosomal DNA (SSU rDNA) multicopy genes have been widely used in routine veterinary practise for FeL diagnosis (Pimenta et al., 2015; Brianti et al., 2019; Pereira et al., 2019c) as well as in epidemiological studies concerning Leishmania infection in cats Vilhena et al., 2013; Pereira et al., 2020) . Nevertheless, two-step PCR when used to amplify stretches of multicopy genes has increased the sensitivity of detection, and should be preferred for sample testing under suboptimal conditions (i.e. where the parasite load tends to be low) such as when whole blood is used . On the other hand, quantitative PCR (qPCR) may further provide information about the amount of parasite DNA present in the sample (Galluzzi et al., 2018) . This aspect is particularly relevant for monitoring the efficacy of anti-Leishmania treatments Basso et al., 2016) . However, it is important to highlight that a PCR-positive result may only reflect a transient infection and, for this reason, should be carefully interpreted in a clinical context. PCR products may be subsequently analysed by restriction enzyme Pereira et al., 2020) . The most common serological tests used to detect anti-Leishmania antibodies in cats are based on enzyme-linked immunosorbent assay (ELISA) and immunofluorescent antibody test (IFAT). The latter is considered as the reference test for the serodiagnosis of canine and human leishmaniosis (OIE, 2018; WHO, 2010) . Persichetti et al. (2017) established 1:80 serum dilution as IFAT cut-off for FeL serodiagnosis, and demonstrated that this test helps to detect subclinical or early Leishmania infections in cats. More recently, Iatta et al. (2020) validated IFAT as an accurate test to assess the exposure of cats to L. infantum, reporting positive and negative predictive values of 80.7% and 89.9%, respectively. Compared to IFAT, ELISA (cut-off 40 ELISA units) presents a better performance for the serodiagnosis of clinical FeL . Western blot analysis is mainly intended for research and is rarely available in routine practice. However, this test seems to offer the best diagnostic performance (considering an 18 kDa band as a marker for Fig. 3 Proposed diagnostic algorithm for clinically healthy cats used as blood donors or for breeding, and cats with suspected leishmaniosis positivity) to detect antibodies against L. infantum in cats . Direct agglutination test has also occasionally been used in both clinical and epidemiological contexts for serological diagnosis of FeL (Pimenta et al., 2015; Asgari et al., 2020) . Some authors have considered a cut-off value of 1:100 to distinguish infected from uninfected cats (Kongkaew et al., 2007; Cardoso et al., 2010; Maia et al., 2015a; Lopes et al., 2017; Asgari et al., 2020; Neves et al., 2020) . Indirect hemagglutination was exclusively performed in epidemiological studies in domestic cats in Egypt (Michael et al., 1982; Morsy et al., 1988; Morsy & Abou el Seoud, 1994) . Cats with clinical leishmaniosis tend to present high antibody levels Maia et al., 2015b; Pimenta et al., 2015; Basso et al., 2016) , and specific treatment frequently leads to the reduction of anti--Leishmania antibodies (Pennisi et al., 2004; Richter et al., 2014; Basso et al., 2016; Pereira et al., 2019c) . In some cases, an increase of antibody titres was associated with clinical relapse. Nevertheless, it is essential to emphasise that a positive serological result formally only reflects exposure to pathogens and should be interpreted in a clinical context (Paltrinieri et al., 2016) .

In conclusion, the diagnosis of FeL can be a real challenge for veterinarians and is seldom considered during the differential diagnosis. Therefore, the algorithm illustrated in Fig. 3 is proposed for clinically healthy cats used as blood donors or for breeding purposes, and for cats with suspected leishmaniosis.

Treatment should be considered only after confirmation of disease (see Section 6). Although several treatment regimens have been empirically used for FeL (Table 6) , no controlled studies on their efficacy and safety have yet been performed. Long-term administration of allopurinol as monotherapy is the most common regimen prescribed for FeL (Pennisi et al., 2004; Leiva et al., 2005; Rüfenacht et al., 2005; Marcos et al., 2009; Pocholle et al., 2012; Richter et al., 2014; Maia et al., 2015b; Migliazzo et al., 2015; Pimenta et al., 2015; Basso et al., 2016; Attipa et al., 2017a; Leal et al., 2018; Brianti et al., 2019; Pereira et al., 2019c; Altuzarra et al., 2020; Fernandez-Gallego et al., 2020) . This drug is generally well-tolerated, but possible cases of cutaneous adverse reactions (Leal et al., 2018; Brianti et al., 2019) , coprostasis , and elevated liver enzymes (Rüfenacht et al., 2005) have been sporadically reported. Favourable results (i.e. clinical cure or improvement of clinical status) with allopurinol as monotherapy have been commonly obtained (Pennisi et al., 2004; Leiva et al., 2005; Rüfenacht et al., 2005; Pocholle et al., 2012; Richter et al., 2014; Migliazzo et al., 2015; Pimenta et al., 2015; Attipa et al., 2017a; Fernandez-Gallego et al., 2020; Altuzarra et al., 2020) . Nevertheless, relapse after discontinuation or low-dose administration (Pennisi et al., 2004; Leiva et al., 2005; Brianti et al., 2019; Pereira et al., 2019c) and no or poor response to allopurinol therapy have been occasionally reported, even in cats with no apparent history of concomitant infections or immunosuppressive therapies (Rüfenacht et al., 2005; Marcos et al., 2009; Basso et al., 2016; Fernandez-Gallego et al., 2020) . Therefore, the combination of meglumine antimoniate and allopurinol has been proposed for FeL treatment, appearing to be more effective (Basso et al., 2016; Pereira et al., 2019c) , but acute kidney injury has already been reported (Leal et al., 2018) . Although controversial, this drug is suspected of inducing nephrotoxicity in dogs (reviewed by Roura et al., 2021) . Thus, its use in cats with altered renal function should be carefully considered. Meglumine antimoniate plus ketoconazole was used in a cat with cutaneous and systemic signs of FeL, resulting in apparent clinical cure (Herv as et al., 1999) . Miltefosine was recently adopted as an alternative to meglumine antimoniate in an azotemic cat, resulting in rapid clinical improvement (Leal et al., 2018) . In this case, transient vomiting episodes were reported in the first week of treatment but were managed using antiemetics (i.e. maropitant). Nevertheless, Fernandez-Gallego et al. (2020) recently reported a case of FeL with concomitant FIV infection not responsive to miltefosine plus allopurinol (combination therapy). Pennisi et al. (2004) reported treatment failure in a seropositive cat for FIV, T. gondii and B. henselae suffering from leishmaniosis. In this case, three distinct regimens were used (i.e. metronidazole plus spiramycin, fluconazole and itraconazole) (Pennisi et al., 2004) . In another cat with leishmaniosis associated with an invasive squamous cell carcinoma, domperidone was used after unsuccessful allopurinol monotherapy, but clinical signs remained after one month of treatment . The dietary supplement active hexose correlated compound (AHCC) was recently suggested as a possible alternative maintenance therapy to allopurinol (Leal et al., 2018) . Surgical removal of lesions was also reported as an additional therapeutic approach (Herv as et al., 2001; Rüfenacht et al., 2005; Basso et al., 2016) .

Like in dogs, Leishmania parasites may persist in treated cats Pimenta et al., 2015; Attipa et al., 2017a) , suggesting that treatment may lead to clinical cure but may not eliminate the infection.

Overall, FeL has a good prognosis even in cases with underlying viral infections (i.e. FIV or FeLV) (Herv as et al., 1999; Pennisi et al., 2004; Rüfenacht et al., 2005; Richter et al., 2014; Migliazzo et al., 2015; Pimenta et al., 2015; Basso et al., 2016; Attipa et al., 2017a; Leal et al., 2018; Pereira et al., 2019c; Altuzarra et al., 2020; Fernandez-Gallego et al., 2020) . On the other hand, panleukopaenia, acute kidney injury and lack of treatment seem to be critical factors associated with poor prognosis Herv as et al., 1999; Poli et al., 2002; Pennisi et al., 2004; Pimenta et al., 2015; Fernandez-Gallego et al., 2020) .

No vaccines or drugs preventing leishmaniosis are currently available for use in cats, and most repellents avoiding infection in dogs are toxic to these felids. In endemic areas, cats are frequently exposed to phlebotomine sand fly bites, and this is associated with an increased risk of Leishmania infection (Pereira et al., 2019b) . Chemoprophylaxis may be achieved by using a matrix collar containing 10% imidacloprid and 4.5% flumethrin. This formulation showed to be safe and effective in reducing infection risk by L. infantum in cats (Brianti et al., 2017) . Nevertheless, keeping cats indoors from dusk to dawn during the period of vector activity (April to November in Mediterranean areas, see Alten et al., 2016) , as well as using physical barriers such as nets (i.e. mesh size 1,240 holes/in 2 ) on windows and doors (Faiman et al., 2009 ) may eschew exposure to phlebotomine sand fly bites, thereby minimising the risk of Leishmania infection. Spraying with residual insecticides on walls and roofs of human houses and animal shelters has been proposed as an additional measure for preventing CanL (Maroli et al., 2010) . However, their use in environments with cats should be carefully considered since most of these products contain compounds (i.e. pyrethrins or pyrethroids) that can induce feline toxicosis. Isoxazolines, namely afoxolaner and fluralaner, have been regarded as a new promising class of drugs for controlling CanL and human leishmaniosis in endemic areas (Miglianico et al., 2018; Bongiorno et al., 2020; Queiroga et al., 2020) . A spot-on formulation of fluralaner (112.5-500 mg) is licensed for ectoparasite (i.e. ticks, fleas and mites) control in cats. This systemic insecticide induced long-term mortality of Lutzomyia longipalpis and Phlebotomus perniciosus (vectors of L. infantum in the New and Old Worlds, respectively) after feeding on treated dogs (Bongiorno et al., 2020; Queiroga et al., 2020) . Similar results are expected to be observed in cats. Although studies are undoubtedly needed, this drug may also hypothetically represent an affordable indirect method for reducing Leishmania infection in cats in endemic areas. The detection and treatment of cats with leishmaniosis is also likely a beneficial control measure, as they may serve as a source of infection to phlebotomine sand fly vectors (Maroli et al., 2007; da Silva et al., 2010; Mendonça et al., 2020) . In the absence of evidence indicating otherwise, Leishmania-infected cats should not be used for breeding or as blood donors due to the potential risk of transmission through blood transfusion and venereal/congenital infection, as reported in dogs (Owens et al., 2001; Naucke & Lorentz, 2012) .

In summary, and according to the current knowledge, the following prophylactic measures are proposed to prevent and control &feline infection:

In endemic areas, keeping cats indoors from dusk to dawn during the phlebotomine sand fly season should be encouraged. Use of physical barriers on houses and animal shelters located in endemic areas with high vector density. Use of a matrix collar containing 10% imidacloprid and 4.5% flumethrin as well topical solutions containing 112.5-500 mg of fluralaner in cats living in or travelling to (cover the time of travel) endemic areas during the known transmission season. After the return from endemic areas, cats should be clinically evaluated and tested.

Cats eligible for breeding and blood transfusion should be periodically tested. Infected cats should not be used for breeding or as blood donors. Cats with leishmaniosis should be treated and periodically monitored.

Zoonotic visceral leishmaniosis (ZVL) caused by L. infantum is a lifethreatening human disease endemic in the Mediterranean Basin, the Middle East, western Asia, and Brazil (WHO, 2010) . Domestic dogs are considered the primary source of human infection, which typically occurs via the bites of female phlebotomine sand flies (WHO, 2010). Nevertheless, during the last years, cats have been deserved attention due to their potential enrolment in ZVL epidemiology, appearing now as possible primary or secondary reservoir hosts (Asfaram et al., 2019) . This Fluconazole ( hypothesis arises by the following reasons (Maroli et al., 2007; da Silva et al., 2010; GfK, 2016; Pereira et al., 2019b; 2019c; Carneiro et al., 2020; Fernandez-Gallego et al., 2020; Mendonça et al., 2020) :

Cats are frequently exposed to the bites of competent vectors. Cats are naturally susceptible to L. infantum infection. Feline infection often runs a subclinical course. Parasites are frequently found in the skin and blood of infected cats. Naturally infected cats are infectious to competent vectors. Naturally infected cats may be the source of infection to other mammals through competent vectors. Strains of feline origin seem to be indistinguishable from those isolated from dogs, humans, and competent vectors. Cats are among the most popular animals owned as a pet.

Cats are often present in domestic/peridomestic areas where transmission cycles occur.

During the last years, several studies concerning Leishmania infection in cats were conducted. Feline leishmaniosis has also gained importance appearing nowadays as an emergent disease. Nevertheless, its immunopathogenesis is poorly known. This protozoonosis is manifested by a broad spectrum of clinical signs and clinicopathological abnormalities, which, associated with the lack of standardised protocols, make its diagnosis further challenging for veterinarians. In this review, a diagnostic algorithm for FeL is proposed for clinical decision support. Treatment options currently available are empirical and suboptimal. The main form to prevent disease is to avoid infection. However, in contrast to dogs, very limited options are currently available to keep infective sand flies away from cats. Thus, a set of prevention guidelines are herein suggested. 

The authors declare that they have no competing interests.

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