Garcia‑Torres et al. Parasites & Vectors (2022) 15:253 https://doi.org/10.1186/s13071-022-05369-6 Parasites & Vectors RESEARCH Open Access Review and statistical analysis of clinical management of feline leishmaniosis caused by Leishmania infantum Maria Garcia‑Torres1, María Cristina López1, Séverine Tasker2,3, Michael Rex Lappin4, Carles Blasi‑Brugué1 and Xavier Roura1* Abstract Background: There is limited information about feline leishmaniosis (FeL) management in clinical practice. Leishma- nia infantum is the species of Leishmania most frequently reported in both dogs and cats in countries of the Mediter‑ ranean region (henceforth ‘Mediterranean countries’), Central and South America, and Iran. This study was conducted to provide veterinary clinicians with an updated overview of evidence-based information on leishmaniosis in cats. Methods: A review was performed using PubMed, Science Direct, Google Scholar and Web of Science. Case reports of FeL caused by L. infantum were sought for the period 1912 to 1 June 2021. Results: Sixty-three case reports are included in this review. Fifty-nine out of the 63 cats were from Europe, mostly from Mediterranean countries (88.9%). Most of them were domestic short-haired cats (90%) with a mean age of 7.9 years, and had access to the outdoors (77.3%). Sixty-six percent of the cats had comorbidities, of which feline immunodeficiency virus infection was the most frequent (37.7%). Dermatological lesions (69.8%) was the most frequent clinical sign, and hyperproteinemia (46.3%) the most frequent clinicopathological abnormality. Serology was the most performed diagnostic method (76.2%) and was positive for 93.7% of cats. Medical treatment was applied in 71.4% of cats, and allopurinol was the most used drug (74.4%). Survival time was greater for treated cats (520 days; 71.4% of cats) than non-treated cats (210 days; 25.4%). Conclusions: The majority of the cats had comorbidities, of which feline immunodeficiency virus was the most frequent. Dermatological lesions were frequently reported, and systemic clinical signs and clinicopathological abnor‑ malities were also common. Serology may be useful for the diagnosis of FeL in clinical practice, and a positive titer of ≥ 1/40 may be a useful cut-off for sick cats. The reported treatments and dosages varied, but there was a good clini‑ cal response and longer survival in most of the cats treated with allopurinol monotherapy. Keywords: Cats, Leishmaniasis, Serology, Allopurinol, Practitioners Background Leishmaniosis is a zoonotic vector-borne disease with a worldwide distribution. The causal agents of leishmanio- sis are intracellular protozoans of the genus Leishmania, which are transmitted by female phlebotomine sand flies. *Correspondence: Xavier.Roura@uab.cat Although dogs are regarded as the main reservoir host, 1 Hospital Clínic Veterinari, Universitat Autònoma de Barcelona, Barcelona, during the last decades feline leishmaniosis (FeL) has Spain gained more attention from veterinary practitioners and Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. The Creative Commons Public Domain Dedication waiver (http://​creat​iveco​ mmons.​org/​publi​cdoma​in/​zero/1.​0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Garcia‑Torres et al. Parasites & Vectors (2022) 15:253 Page 2 of 13 researchers in areas endemic for leishmaniosis. Although Methods the number of cats with leishmaniosis is currently con- Search strategy sidered negligible in endemic areas, a high percentage Independent literature searches were conducted between of cats test positive for the disease [serology, polymerase March and August 2021 by two of the authors (MGT and chain reaction (PCR), or both] [1–7]. Several Leishmania XR) using the databases and keywords listed in Table 1. spp. can infect cats (Leishmania infantum, Leishmania When there were potential discrepancies between the mexicana, Leishmania venezuelensis, Leishmania tropica, selected articles, a third author (MCL) participated in Leishmania major, Leishmania amazonensis, and Leish- the final decision. Additional studies were identified by mania braziliensis), and L. infantum is the species most contacting the authors of the publications, and by search- frequently reported in both dogs and cats in countries of ing the publications’ reference lists. First, the titles and the Mediterranean region (henceforth ‘Mediterranean abstracts of all the articles identified in the searches were countries’), Central and South America, notably Brazil, evaluated, and then the full texts of those considered and Iran [8–14]. potentially relevant were examined thoroughly. Although it is likely that the first case of L. infantum infection in a cat was that described in 1912 by Ser- gent et al. [15], the number of case reports of FeL has Inclusion and exclusion criteria been increasing globally, especially in the last 30 years The inclusion criteria were as follows: feline case reports [7, 16–56]. However, compared to canine leishmaniosis or case series of FeL caused by L. infantum from 1912 to (CanL), there is still limited information on the clinical 1 June 2021, including signalment, a description of clini- management of FeL. Furthermore, much of the available cal signs, diagnostic methods, treatment protocols and information on FeL is not specific to L. infantum infec- outcome for each cat. The exclusion criteria were as fol- tion, and is mostly from reports providing little scien- lows: duplicate records, case reports of leishmaniosis tific evidence, such as descriptive case series, isolated caused by Leishmania species other than L. infantum, case reports, extrapolations from CanL studies, or those studies that contained information that was confusing or based on the personal experience of respected experts, not sufficiently comprehensible for analysis, and reviews whilst few are based on recent research in cats [8–11, 55, or meta-analyses that did not provide specific data on the 57–59]. Moreover, few of the published research stud- factors that had been investigated for each cat. Data on ies describe the clinical management of leishmaniosis in treatment and outcome were not available for some of cats, and instead focus on the epidemiology and preva- the included cases. The case reports selected in this way lence of leishmaniosis in cats in regions that are endemic were included in a Microsoft Excel database and dupli- or non-endemic for CanL [1, 4, 5, 13, 57, 60–82]. cate data were eliminated. The final collated publications The following are crucial for the management of were used for the statistical analysis, for which data from FeL, especially within the current context of the lack of each of the included studies were extracted. clinical guidelines for this disease: understanding how leishmaniosis caused by L. infantum affects cats; identi- fying the most useful diagnostic tests and most effective Data extraction treatments; and determining the prognostic factors and A pre-established protocol was used to extract the fol- expected prognosis. We conducted a review to assess the lowing data: when and where the research was carried risk factors, clinical signs and clinicopathological altera- out (year, country and geographic region), signalment, tions, diagnostic methods, treatment, and outcome of all clinical presentation, breed, sex, age, indoor/outdoor, known published cases of FeL, to provide veterinary cli- comorbidities, clinical signs, clinicopathological altera- nicians with an updated overview of this disease. tions, diagnostic method, treatment, and outcome. Table 1 Search strategy Source Index terms PubMed (https://​pubmed.​ncbi.​nlm.​nih.​gov) Feline leishmaniosis OR feline leishmaniasis OR cat, Leishmania OR feline, Leishmania infantum Science Direct (https://​www.​scien​cedir​ect.​com/) OR feline, case series OR feline, case reports Google Scholar (https://​schol​ar.​google.​com) Web of Science (https://​apps.​webof​knowl​edge.​com/) Garcia‑Torres et al. Parasites & Vectors (2022) 15:253 Page 3 of 13 Statistical analysis allopurinol plus miltefosine, (iv) meglumine antimoniate, Continuous variables were summarized by mean, range, (v) other, and (vi) no treatment. When survival data were and SD. For association and risk factor analysis for infec- not exactly defined, the highest known values were used tion, geographic data were grouped into Mediterranean as the survival data for the analyses. P < 0.05 was consid- and non-Mediterranean countries; breed data were ered the critical level of significance. grouped into domestic short haired (DSH) and non- DSH (Siamese, Siberian, crossbreed, unknown breeds); lifestyle was divided into indoor or outdoor; and clini- Results cal signs were grouped into cutaneous, mucocutaneous, Case selection ocular, respiratory and systemic. To group clinical signs, The online literature search identified 552 potentially rel- we followed the classification used by the clinicians who evant publications. A total of 355 duplicate publications authored each case report; lymphadenomegaly, fever, were excluded. After the initial screening of the data, lethargy, poor body condition, pallor, hepato-spleno- based on title and/or abstract evaluation, another 130 megaly, weight loss and abdominal distension were con- publications were excluded. A further 25 were excluded sidered systemic signs. Comorbidities were defined as during a second selection process based on the full-text diseases other than FeL, other medical conditions, pre- evaluation of the 67 remaining publications. A total of scribed medication, and pathogens that could modify the 42 articles (63 cats) were finally found to be eligible for immune response inclusion in this review and the data subjected to statisti- In the statistical evaluation of diagnostic method relia- cal analysis (Fig. 1; Table 2). bility, cytology and/or histopathology were considered as gold standards for the direct identification of parasites in Geographic region accordance with experts’ recommendations for FeL. An All the cases were of domestic cats living in Europe (59), indirect fluorescent antibody technique (IFAT) had been Brazil (1), Vietnam (1), Reunion Island (1), and Algeria used in the majority of cases, so to enable the statistical (1). The European cases were from Spain (24), Italy (16), analysis of positive quantitative serological results, all the Portugal (9), France (6), Switzerland (3), and Cyprus (1). data were transformed according to the same titer scale There was a statistically significant association between based on World Organization for Animal Health recom- location and the number of cases, with a higher preva- mendations [83] and divided into titer ranges of 1/40 lence in Mediterranean (56/63, 88.9%) compared to to ≤ 1/80, > 1/80 to ≤ 1/160, > 1/160 to ≤ 1/320, > 1/320 non-Mediterranean (7/63, 11.1%) countries (χ2 = 38.111, to ≤ 1/640, and > 1/640. For those cases where quantita- df = 1, P < 0.001) (Table 3). tive serologic data were not supplied, and only a positive or negative result from a test such as western blot, the results were grouped as qualitative. All the statistical analyses were performed using IBM Total number of studies SPSS version 20 for Mac. Univariate analyses were per- identified (n = 552) formed, and the results are presented as the number of Exclusion of duplicates affected cats in relation to the total number of cats for (n = 355) which the finding was described. Data were evaluated Studies selected for title and for normal distribution using a Kolmogorov–Smirnov abstract reading (n = 197) Exclusion after screening of title and abstract (n = 115) test. In the univariate analyses, when only two independ- ent continuous variables were compared, an independ- Exclusion of species other than L. infantum (n = 15) ent-sample t-test was performedaccording to the data Full-text articles assessed distribution. For the categorical variables, a chi-square for eligibility (n = 67) test of association was used, and for paired samples the Exclusion after full reading of articles (n = 25) Wilcoxon test was used. SPSS was used to calculate the expected frequencies. The rule used was that, at most, Papers selected for review and only 20% of expected frequencies should be less than 5. statistical analysis (n = 42) The Pearson correlation (r) test of association was used for survival and age analyses. A Kaplan–Meier survival analysis with log ranks was used to test for significant dif- Cases included for review and ferences between survival curves for treatment applied. statistical analysis (n = 63) The treatments were grouped as follows: (i) allopuri- Fig. 1 Flow chart showing the search and selection process for the nol, (ii) allopurinol plus meglumine antimoniate, (iii) inclusion of articles in this study Garcia‑Torres et al. Parasites & Vectors (2022) 15:253 Page 4 of 13 Table 2 Cases included in the statistical analysis according to continent, country, type of study and number of cats described Continent Country Type of study (n) No. of cats References Europe Italy Case reports (6), case series (1), system‑ 16 [7, 26, 27, 32, 36, 44, 49, 55] atic review (1) France Case reports (6) 6 [19, 21, 22, 29, 39, 40] Spain Case reports (13), case series (1) 24 [23–25, 31, 33, 34, 37, 38, 46, 51–54, 56] Portugal Case reports (6), case series (1) 9 [20, 35, 42, 43, 45, 48, 50] Switzerland Case report (1), case series (1) 3 [30, 41] Cyprus Case report (1) 1 [47] Africa Algeria Case report (1) 1 [17] Reunion Island Case report (1) 1 [18] South America Brazil Case report (1) 1 [28] Asia Vietnam Case report (1) 1 [16] Table 3 Univariate analysis of the association between Table 4 Comorbidities in cats with leishmaniosis geographic region, breed, sex, and lifestyle of cats with Comorbidities No. of cats (from % leishmaniosis a total of 53) Covariate Levels n (%) χ2 (df) P-value Present 35 66.0 Geographic Non-Mediterra‑ 7/63 (11.1) Absent 18 34.0 region nean FIV +ve 20 37.7 Mediterranean 56/63 (88.9) 38.111 (1) < 0.001* FIV −ve 33 62.3 Breed Siamese 4/63 (6.3) FeLV +ve 4 7.5 Siberian 1/63 (1.6) FeLV −ve 49 92.5 Crossbreed 1/63 (1.6) Corticosteroid treatment Unknown 3/63 (4.8) Yes 11 20.8 DSH 54/63 (85.7) 170.571 (4) < 0.001* No 42 79.2 Sex Male 29/62 (46.7) Other medical conditions and pathogens Female 33/62 (53.2) 0.258 (1) 0.611 Bartonella henselae 2 3.8 Lifestyle Indoor 5/22 (22.7) Candidatus Mycoplasma haemominutum 2 3.8 Outdoor 17/22 (77.3) 6.545 (1) < 0.011* Feline coronavirus 3 5.6 Mediterranean Mediterranean region, DSH domestic short haired Toxoplasma spp. 4 7.5 *P < 0.05 Hepatozoon spp. 1 1.9 Pemphigus 1 1.9 Pregnancy 1 1.9 Signalment Squamous cell carcinoma 2 3.8 The age of the cats at clinical presentation was known Diabetes mellitus 1 1.9 in 56/63 cases, and ranged from 2 to 21 years (mean 7.9 Epidermoid carcinoma 1 1.9 ± 4.1 years). Breed was described for 60 out of the 63 FIV Feline immunodeficiency virus, FeLV feline leukemia virus cases, and was as follows: 54 DSH (85.7%), four Siamese (6.3%), one Siberian (1.6%) and one crossbreed (1.6%) cat. DSH were more likely to be infected than non- DSH breeds (χ2 = 170.571, df = 4, P < 0.001). Sex was reported in 62 out of 63 cases, and there was a slightly between an outdoor lifestyle and infection (χ2 = 6.545, higher prevalence in females (53.2%) than in males df = 1, P ≤ 0.011) (Table 3). (46.7%), although this difference was not statistically Information on comorbidity status was available for significant (χ2 = 0.258, df = 1, P = 0.611). Lifestyle was 53 cats (Table 4); of these 35 (66.0%) had comorbidi- known for 22 cats, of which 17 were outdoor (77.3%) ties and 18 (34.0%) did not. Of the 35 cats with comor- and five indoor cats (22.7%). There was an association bidities, 22 (62.9%) had only one comorbidity, whereas 13 (37.1%) had two or more. Positive feline immuno- deficiency virus (FIV) antibody status was the most prevalent comorbidity, but the association between Garcia‑Torres et al. Parasites & Vectors (2022) 15:253 Page 5 of 13 this and leishmaniosis was not statistically significant Table 5 Clinical signs and lesions described in cats (n = 63) with (χ2 = 0.277, df = 1, P = 0.599). leishmaniosis Clinical signs and lesions Frequency Clinical presentation No. of cats % The clinical signs and lesions that were reported are given in Table 5. The most frequent clinical signs were cutane- Cutaneous 44 69.8 ous (44/63; 69.8%), followed by systemic (35/63; 55.5%), Ulcerative dermatitis 20 31.7 ocular (22/63; 34.9%), mucocutaneous (18/63; 28.6%) Nodular dermatitis 14 22.2 and respiratory (8/63; 12.7%). Many of the cats showed Alopecia 9 14.3 a combination of clinical signs (37/63; 58.7%). There was Desquamative dermatitis 7 11.1 a statistically significant association between dermato- Crusty dermatitis 5 7.9 logical signs and FIV (χ2 = 7.185, df = 1, P = 0.007), and Pruritus 2 3.1 between ocular signs and the neutered status of females Bloody cyst 2 3.1 (χ2 = 17.814, df = 3, P < 0.001). However, no other statisti- Papular dermatitis 1 1.6 cally significant associations were found between groups Systemic 35 55.5 of clinical signs and age, sex, breed, or comorbidities Lymph node enlargement 18 28.5 (Table 6). Lymph node size was described for 45/63 cats Anorexia/hyperorexia 14 22.2 from physical examination; the percentage of cats with Weight loss 14 22.2 lymph nodes of normal size (27/45; 60.0%) was greater Depression 13 20.6 than that of cats with lymphadenomegaly (18/45; 40.0%). Fever 7 11.1 When clinicopathological abnormalities were reported, Pallor 5 7.9 hyperproteinemia was the most frequent (19/41; 46.3%), Vomiting/diarrhea 3 4.7 followed by anemia (16/48; 33.3%), neutrophilia (9/48, Polyuria/polydipsia 1 1.6 18%), thrombocytopenia (8/48, 16.6%), proteinuria (7/46; Icterus 1 1.6 15.2%) and azotemia (7/47; 14.9%). Hypergammaglobu- Ocular 22 34.9 linemia was the most frequent alteration detected by Uveitis 13 20.6 serum protein electrophoresis (27/38; 71.0%) followed by Conjunctivitis 7 11.1 hypoalbuminemia (9/47; 19.1%). Other reported clinico- Nodular blepharitis 6 9.5 pathological alterations were neutropenia (4/48, 8.3%), Ulcerative blepharitis 3 4.7 eosinophilia (3/48, 6.25%), pancytopenia (1/48, 2%) and Keratoconjunctivitis 1 1.6 an increase in alanine transaminase level (2/48, 4.1%). Ulcerative keratitis 1 1.6 Mucocutaneous 18 28.6 Diagnostic methods Stomatitis/gingivostomatitis 11 17.4 Cytology, for the detection of Leishmania amastig- Glossitis 3 4.7 otes, was the most common first line or preferred diag- Nasal ulcers 3 4.7 nostic option of practitioners for the diagnosis of FeL Nasal pustules 2 3.1 (28/63, 44.4%), followed by histopathology (20/63, 31.7%), Nasal depigmentation 1 1.6 serology (17/63, 26.9%) and PCR (3/63, 4.7%). There was Oral ulcers 1 1.6 no statistically significant association (χ2 = 8.980, df = 2, Respiratory 8 12.7 P = 0.062) between results from the PCR and those from Nasal discharge 4 6.3 cytological and/or histopathological examination (widely Stridor 3 4.7 used as confirmatory tests for FeL and considered gold Stertor 1 1.6 standards here). However, a statistically significant asso- Sneezing 1 1.6 ciation between cytology and/or histopathology and Reverse sneezing 1 1.6 seropositivity (χ2 = 26.913, df = 14, P = 0.020) was found. Dyspnea 1 1.6 Of the complete diagnostic procedures (both first Bronchitis 1 1.6 line and additional diagnostic tests), antibody detection techniques were performed most (48/63; 76.2%), and comprised IFAT (28/48), qualitative serology (11/48), infantum antibody positive status and diagnosis of FeL enzyme-linked immunosorbent assay (5/48), and direct by cytology and/or histopathology (χ2 = 36.750, df = 2, agglutination (4/48). Antibody tests were positive for P < 0.001). In cats seropositive according to quantita- 45/48 cats (93.7%) and negative for 3/48 (6.3%); there tive tests (35/45, 77.8%), the titers ranged from 1/40 was a statistically significant association between L. to ≤ 1/80 in 5/35 (14.3%), from > 1/80 to ≤ 1/160 in Garcia‑Torres et al. Parasites & Vectors (2022) 15:253 Page 6 of 13 Table 6 Analysis of association (χ2) between sex, age, breed, comorbidities (any), FIV, FeLV, and steroid treatment with groups of clinical signs Variable Cutaneous Mucocutaneous Ocular Respiratory Systemic Sex χ2 = 6.065, df = 3 χ2 = 0.386, df = 3, χ2 = 17.814, df = 3, χ2 = 3.285, df = 3, χ2 = 1.444, df = 3, P = 0.108 P = 0.943 P =  < 0.001* P = 0.350 P = 0.695 Age t(63) = 1.206, P = 0.233 t(63) = 1.525, P = 0.133 t(63) = 1.906, P = 0.062 t(63) = 0.370, P = 0.713 t(63) = 0.912, P = 0.366 Breed χ2 = 4.534, df = 4, χ2 = 4.200, df = 4, χ2 = 3.230, df = 4, χ2 = 8.126, df = 4, χ2 = 2.663, df = 4, P = 0.339 P = 0.380 P = 0.520 P = 0.087 P = 0.616 Comorbidities χ2 = 1.914, df = 1, χ2 = 0.005, df = 1, χ2 = 0.015, df = 1, χ2 = 0.105, df = 1, χ2 = 0.010, df = 1, P = 0.167 P = 0.945 P = 0.901 P = 0.746 P = 0.922 FIV χ2 = 7.185, df = 1, χ2 = 1.150, df = 1, χ2 = 0.070, df = 1, χ2 = 0.090, df = 1, χ2 = 1.539, df = 1, P = 0.007* P = 0.283 P = 0.791 P = 0.764 P = 0.215 FeLV χ2 = 0.638, df = 1, χ2 = 0.155, df = 1, χ2 = 0.277, df = 1, χ2 = 0.658, df = 1, χ2 = 1.002, df = 1, P = 0.424 P = 0.694 P = 0.599 P = 0.417 P = 0.317 Steroid treatment χ2 = 0.117, df = 1, χ2 = 2.622, df = 1, χ2 = 0.011, df = 1, χ2 = 0.300, df = 1, χ2 = 0.895, df = 1, P = 0.732 P = 0.105 P = 0.916 P = 0.584 P = 0.344 For abbreviations, see Table 4 *P < 0.05 Table 7 Frequency of tested tissues and positive results from Table 8 Frequency of tested tissues and parasite detection polymerase chain reaction (PCR) using cytology Tested tissue PCR (n = 38) PCR +ve (n = 36, 94.7%) Tested tissue Cytology (n = 44) Cytology +ve (n = 39, 88.6%) Blood 18/38, 47.3% 16/18, 88.8% Skin samples 6/38, 15.7% 6/6, 100% Skin lesions 20/44, 45.4% 18/20, 90% Unknown origin 6/38, 15.7% 6/6, 100% Lymph node 18/44, 40.9% 16/18, 88.8% Lymph node 4/38, 10.5% 4/4, 100% Ocular lesions 7/44, 15.9% 7/7, 100% Bone marrow 4/38, 10.5% 4/4, 100% Bone marrow 6/44, 13.6% 5/6, 83.3% Ocular samples 2/38, 5.2% 2/2, 100% Spleen 2/44, 4.5% 2/2, 100% Spleen 2/38, 5.2% 2/2, 100% Liver 1/44, 2.2% 1/1, 100% Respiratory samples 1/38, 2.6% 1/1, 100% Blood 1/44, 2.2% 1/1, 100% Respiratory lesions 1/44, 2.2% 1/1, 100% 3/35 (8.6%), from > 1/160 to ≤ 1/320 in 5/35 (14.3%), Table 9 Frequency of tested tissues and parasite detection from > 1/320 to ≤ 1/640 in 5/35 (14.3%), and were using histopathology > 1/640 in 17/35 cats (48.5%). No statistically significant Tested tissue Histopathology Histopathology +ve (n = 31, association was found between serological titers and (n = 35) 88.6%) category of clinical signs or clinicopathological abnor- Skin lesions 22/35, 62.8% 20/22, 90.9% malities (P > 0.05). Qualitative positive serology was Ocular lesions 5/35, 14.2% 4/5, 80% reported for 10/45 cats (22.2%). Respiratory 4/35, 11.4% 3/4, 75% Polymerase chain reaction (using blood, lymph node, lesions bone marrow, spleen tissue; ocular, lung or skin sam- Oral lesions 2/35, 5.7% 2/2, 100% ples) was performed for 38 of the 63 cats (60.3%), and Bone marrow 2/35, 5.7% 1/2, 50% was positive for 36 of them (94.7%) (Table 7). Cytology Spleen 2/35, 5.7% 2/2, 100% was performed for 44/63 cats (69.8%) and histopathol- Kidney 1/35, 2.8% 1/1, 100% ogy for 35/63 cats (55.5%) using different types of tis- sue. Cytology and histopathology were positive for Leishmania amastigotes in 39/44 cats (88.6%) and 31/35 serological titers, no statistically significant association (88.6%), respectively (Tables 8, 9). With respect to was found between PCR, cytology or histopathology Garcia‑Torres et al. Parasites & Vectors (2022) 15:253 Page 7 of 13 with any category of clinical sign or clinicopathological Outcome abnormality (P > 0.05). Survival time ranged from 0 to 2700 days, with a mean of 432 days (± 575). Mean survival time was significantly longer for treated cats than non-treated cats (520 days Treatment and 210 days, respectively) (χ2 = 15.311, df = 1, P = 0.002) Medical treatment was administered in 45/63 cats (Fig. 2). However, no significant association was found (71.4%); 16/63 (25.4%) did not receive any treatment, and between survival time and any other variable (Table 10). treatment was not stipulated for 2/63 (3.2%). Allopuri- nol was used in 37/45 cats (74.4%), followed by meglu- Discussion mine antimoniate in 13/45 (28.9%) and miltefosine in The results of this study indicate that leishmanio- only one cat of the 45 (2.2%). Although the dosages var- sis should be included in the differential diagnosis of ied, the most frequent were 10 mg/kg twice a day (BID) sick cats living in, or with a history of travel to, areas per os (PO) for at least 6 months for allopurinol (20/37 where CanL is endemic [1–3, 84]. Prevalences of FeL in cats; 54.0%), 50 mg/kg once a day (SID) subcutaneously endemic areas as shown by positive PCR range from 0 (SC) for 30 days for meglumine antimoniate (5/13 cats; to 100% (mean 21.3%), whilst those indicated by posi- 38.5%), and 2 mg/kg SID PO for 28 days for miltefos- tive serology range from 0 to 70.5% (mean 13.7%) [1, 10, ine in the only cat in which it was used. Allopurinol was 85]. Prevalences determined by both of these types of used as monotherapy in 28/37 cats (75.7%) and in com- tests are lower for cats than dogs (63% and 27% for PCR bination with meglumine antimoniate or miltefosine and serology, respectively) [85]. There are also fewer in 8/37 (21.6%) and 1/37 (2.7%) cats, respectively. Meg- clinical feline cases than canine cases in the literature lumine antimoniate was used as monotherapy in 5/13 [8–11, 59]. Thus, all this suggests that the prevalence cats (38.5%) and in combination with allopurinol in 8/13 of FeL could be about half that of CanL for the same (61.5%). Adverse effects associated with treatment were geographical areas [60, 63, 74, 79–81]. Furthermore, reported in 10/45 cats (22.2%), and were mainly associ- as previously reported for CanL [86, 87], increased ated with allopurinol (7/10), and affected the kidney movement of pet cats between countries, especially (4/10), skin (2/10) and liver (1/10). inside Europe, could lead to clinical cases of FeL being Fig. 2 Kaplan–Meier survival curves of cats treated with allopurinol, allopurinol plus meglumine antimoniate, allopurinol plus miltefosine, meglumine antimoniate, other, or no treatment. Median survival time of the treated cats was as follows: allopurinol (28/63; 619 days); allopurinol plus meglumine antimoniate (8/63; 614 days); allopurinol plus miltefosine (1/63; 45 days); meglumine antimoniate (5/63; 1372 days); other such as fluconazole, metronidazole, spiramycin or lomidine (3/63; 660 days); no treatment (10/63; 411 days) Garcia‑Torres et al. Parasites & Vectors (2022) 15:253 Page 8 of 13 Table 10 Analysis of association (χ2) between treatment, age, It is well recognized that susceptibility to progres- breed, sex, lifestyle, comorbidities (any), clinical signs (any), sive Leishmania infection and the development of clini- clinicopathological abnormalities (any), PCR positive test, cal signs in dogs is mostly linked to an imbalance in the serological titer and survival adaptive immune response, and probably associated Variable Survival with a predominant Th2 response and an impaired Th1 immune response [88]. However, in contrast to CanL, Treatment (yes/no) χ2 = 15.311, df = 1, P = 0.002* to the best of our knowledge, no prospective controlled Age r(63) = -0.028, P = 0.856 studies have been published on immune mechanisms Breed χ2 = 17.165, df = 4, P = 0.144 involved in the pathogenesis of FeL. Some investiga- Sex χ2 = 3.112, df = 3, P = 0.960 tions have suggested that cats may have a better immune Lifestyle χ2 = 0.889, df = 1, P = 0.889 response against L. infantum because the Th2 response Comorbidities (any) χ2 = 0.381, df = 1, P = 0.944 plays a protective role [81, 89], or because there are other Cutaneous clinical signs χ2 = 1.693, df = 1, P = 0.638 factors in seropositive cats that can control the develop- Mucocutaneous clinical signs χ2 = 3.100, df = 1, P = 0.377 ment of patent leishmaniosis [90], such as the produc- Ocular clinical signs χ2 = 3.742, df = 1, P = 0.291 tion of higher levels of interferon gamma, which plays a Respiratory clinical signs χ2 = 1.098, df = 1, P = 0.778 direct role in the regulation of Th1 cell development [91]. Systemic clinical signs χ2 = 6.014, df = 1, P = 0.111 Thus, Leishmania spp. infection in cats might be more Anemia χ2 = 0.669, df = 1, P = 0.881 common than associated disease, and cats might be more Hyperproteinemia χ2 = 1.048, df = 1, P = 0.790 resistant to disease development than dogs [9, 59]. Cats Hyperglobulinemia χ2 = 1.495, df = 1, P = 0.683 that develop leishmaniosis are often suspected of hav- Hypergammaglobulinemia χ2 = 2.252, df = 1, P = 0.522 ing impaired immunity because of comorbidities [8–11]. Hypoalbuminemia χ2 = 1.927, df = 1, P = 0.588 However, to date, a significant association has only been Azotemia χ2 = 5.555, df = 1, P = 0.135 reported between L. infantum and FIV co-infection [67, Proteinuria χ2 = 2.233, df = 1, P = 0.526 69, 70, 82, 92], although the results of other studies con- PCR +ve χ2 = 9.932, df = 2, P = 0.128 tradict this association [71–73, 81]. In this review, a high Serological titer χ2 = 18.920, df = 7, P = 0.590 percentage (66.0%) of evaluated cats with leishmanio- *P < 0.05 sis had comorbidities which are associated with poten- tially impaired immune competence, such as previous corticosteroid treatment, diabetes mellitus, epidermoid diagnosed in areas that are not endemic for L. infantum carcinoma, squamous cell carcinoma, pemphigus, or co- [30, 41]. However, although there have been epidemio- infections such as FIV, feline leukemia virus, Bartonella logical studies on FeL in areas that are also endemic for henselae, ‘Candidatus Mycoplasma haemominutum,’ CanL, such as Brazil [1, 84], only one case from Brazil feline coronavirus, Toxoplasma spp. and Hepatozoon was included in the current study. Possible reasons for spp. Furthermore, the current study confirms that FIV, this include the non-detection of other cases from Bra- which was detected in 37.7% of cats, is the most frequent zil due to the criteria used in this study, and/or perhaps comorbidity associated with FeL, although the associa- because feline medicine is less developed there, and/or tion was not statistically significant. because most knowledge on leishmaniosis is focused Leishmaniosis in dogs has a wide range of clinical signs on dogs. Thus, even in areas that are non-endemic for [8, 93–95], but extrapolating these to cats could mean L. infantum, leishmaniosis should be considered as a that only the clinical signs of an infected cat that resem- differential diagnosis in cats with clinical signs or path- ble those of CanL would be used in a differential diagno- ological alterations consistent with this disease. sis for FeL. This could lead to the misdiagnosis of FeL and Few epidemiological studies have reported significant thus the underestimation of its clinical relevance. The associations between L. infantum infection in cats and clinical signs of FeL described in this review are mainly their access to outdoors, that they are male, or their age dermatological (69.8%), followed by systemic (55.5%), when they are adults [60, 64]. Most of the cats affected ocular (34.9%), mucocutaneous (28.6%), and respiratory by leishmaniosis in the present study were DSH with (12.7%). These results agree with those of previous stud- outdoor access, and had a mean age of 7.9 years. In con- ies, where dermatological lesions and systemic clinical trast to other publications [60, 65, 66], we found that signs, including lymph node enlargement, were reported more female cats were diagnosed with leishmaniosis than frequently in cats infected with L. infantum [9, 10, 53]. male cats, although this difference was not statistically These findings support the idea that, when caused by L. significant. infantum, CanL and FeL present similarly, and thus FeL should also be included in the differential diagnosis when Garcia‑Torres et al. Parasites & Vectors (2022) 15:253 Page 9 of 13 a wide range of systemic clinical signs of leishmaniosis for FeL, followed by histopathology, serology, and PCR. present alone or in combination in a cat. Less frequent Furthermore, Leishmania DNA was easily detected by and/or severe, isolated clinical presentations may go PCR, as were amastigotes by cytology and histopathol- unreported or misdiagnosed, and presumably could lead ogy (i.e. in 94.7%, 88.6%, and 88.6% of cats with clinical to underestimation of the clinical relevance of FeL [8]. leishmaniosis, respectively). Although multiple factors have been found to be statisti- Conversely, serology has been suggested as being less cally associated with a wide range of clinical manifesta- useful for cats than for dogs for the diagnosis of leish- tions in FeL [66, 96], this review only found a statistically maniosis in clinical practice, and thus it may be more significant association between dermatological signs and useful as an additional test to support the diagnosis of FIV positive status. A potential explanation for this is that leishmaniosis and the follow up of sick cats with the dermatological lesions associated with leishmaniosis and disease [8–11]. Anti-Leishmania antibody detection immunodeficiency are very similar in cats, so they could techniques such as IFAT, enzyme-linked immunosorb- have been secondary to either condition [55]. ent assay, direct agglutination and western blot have In comparison to CanL, there is limited information been extensively used in a wide range of studies on about clinicopathological abnormalities associated with cats [1, 4, 5, 10, 57, 60, 62–64, 66–68, 70–78, 80–82]. L. infantum infection in cats [41, 57, 97]. Of the cases However, the low levels of antibodies produced in cats analyzed here, hyperproteinemia (46.3%) was the most due to their differing immune responses [74, 90] as frequent laboratory abnormality, and hypergammaglobu- compared to dogs, and/or the fact that few laborato- linemia (71.0%) followed by hypoalbuminemia (19.1%) ries offer validated serological tests for FeL (compared were the most frequent alterations seen on serum pro- to serological tests for CanL) may explain why serol- tein electrophoresis, in agreement with the results of two ogy has previously been overlooked as a diagnostic test studies [41, 57], but in contrast with those of another for FeL in clinical practice [5, 57, 60, 62–64, 68–72]. study [58]. The percentages of cats presenting with neu- For these reasons, it has been recommended that sero- trophilia, thrombocytopenia, proteinuria, and azotemia logic results should be interpreted with caution and in (18%, 16.6%, 15.2% and 14.9%, respectively) reported in combination with other diagnostic test results and the the present study suggest that leishmaniosis should be a assessment of clinical signs for the diagnosis of FeL differential diagnosis for hypergammaglobulinemic cats [8–11, 58]. Although a cut-off titer of 1:80 or above is with any of these conditions. However, although gamma considered adequate to discriminate between infected globulin levels were significantly elevated in FeL, they and non-infected cats [57, 64, 70, 74], the level of this could not be used to differentiate FeL from other inflam- titer is still controversial. In the current study, among matory, neoplastic or vector-borne diseases in cats [97]. first line and additional diagnostic tests, serology (73%) Furthermore, we report here the important finding that, was the diagnostic technique most used by practition- in FeL, unlike in CanL, azotemia and proteinuria are fre- ers (positive serology in 93.5% of the sick cats), and quently concurrent [98–100]. Although in dogs leish- positive serological results showed a statistically sig- maniosis is an important cause of proteinuria, this is not nificant association with cytology and/or histopathol- thought to be the case in cats [57, 58]. However, the pre- ogy results. Furthermore, the positive seroreactivity sent study shows that proteinuria is not that infrequent titer range was wide (1/40 to > 1/640) in sick cats. How- in cats with FeL caused by L. infantum, which suggests ever, no statistically significant association was found that it is important to perform urinalysis and measure between serological titers and any type of clinical sign the urinary protein to creatinine ratio to help in the early or clinicopathological abnormality, showing that there detection, and subsequent management, of chronic kid- is no apparent direct relationship between clinical ney disease in cats with leishmaniosis [101]. alterations and serological titers. Thus, we suggest that In contrast to CanL, there are fewer clearly rec- serology may be more useful as an initial diagnostic test ommended diagnostic tests for FeL [8–11]. Previous than previously thought when cats that are suspected of reviews and expert opinions suggest that, in clinical having leishmaniosis are evaluated in clinical practice, practice, the best means of confirming FeL is the detec- and that a serological titer of ≥ 1/40 could be a suitable tion of Leishmania amastigotes by cytology and/or his- cut-off for the diagnosis of leishmaniosis caused by L. topathology, or the detection of Leishmania DNA by infantum in cats with clinical signs or clinicopathologi- PCR; all of these tests can be performed using a sample cal alterations compatible with this disease. However, of any type of affected tissue, including lymph node tis- further studies are needed to confirm the best serologi- sue, bone marrow or blood [8–10, 102, 103]. In agree- cal positive cut-off titer for the diagnosis of patent FeL. ment with published recommendations, cytology was An empirical therapeutic approach to FeL usually found to be the preferred first line diagnostic technique involves the extrapolation of recommendations for Garcia‑Torres et al. Parasites & Vectors (2022) 15:253 Page 10 of 13 CanL [94, 104] as no studies have been conducted to the prognosis of sick cats diagnosed with leishmaniosis evaluate the efficacy and safety of treatments in cats were identified. [8–11]. In line with the recommendations for CanL, This study had several limitations, including (i) the risk the long-term administration of allopurinol, used as of bias associated with the lack of inclusion of more cases monotherapy (75.7%), or in combination with meglu- due to the search criteria used, (ii) difficulties associated mine antimoniate (21.6%) or miltefosine (2.7%), was the with the statistical analysis due to the fact that most of the drug of choice used for the treatment of 74.4% of the included publications described a single clinical case, (iii) cats, followed by meglumine antimoniate and miltefo- the heterogeneity of data due to different clinical man- sine for 28.9% and 2.2%, respectively. Adverse effects agement among years, (iv) imprecision regarding treat- associated with treatment were reported in 22.2% of the ment effects due to the variability in dosages amongst the cats [30, 48, 51, 53–55]. Although recent reports indi- included cases, and (v) the lack of a comprehensive data cate that allopurinol can have different adverse effects set due to the retrospective nature of this study. in cats [48, 49] compared to those observed in dogs [94, 104], it should be noted that both spontaneous [105] and allopurinol-induced [51, 54] xanthinuria and uro- Conclusions lithiasis have also been described in cats, hence it is The case reports of FeL caused by L. infantum included recommended that urinalysis be performed during the in the present study showed that the cats often had a treatment of FeL with allopurinol, as is done for CanL. comorbidity, with FIV infection being the most fre- Finally, propylene glycol is one of the excipients in the quent of these. Dermatological alterations were the oral formulation of miltefosine that is licensed for the most frequently reported clinical sign in FeL caused by treatment of CanL, and has been reported to poten- L. infantum, although systemic clinical signs and clin- tially cause a decrease in the lifespan of feline red blood icopathological abnormalities, alone or in combination, cells due to the formation of Heinz bodies [8, 106]. were also common. Leishmaniosis should be included as Thus, the use of miltefosine should possibly be avoided a differential diagnosis for sick cats who live in, or have in cats, or at least only used with caution until more traveled from, areas endemic for CanL. The results of scientific evidence on its effects have been published. this study also indicate that serology could be useful as a Survival time ranged from 0 to 2,700 days, with a first line diagnostic test for FeL, and that a positive titer mean of 432 days. Mean survival time was statisti- of ≥ 1/40 could be a suitable cut-off for the diagnosis of cally greater for treated cats than non-treated cats leishmaniosis in sick cats that are suspected of having (520 and 210 days, respectively), which supports pre- the disease. Finally, despite the limitations of this study, vious recommendations that cats with clinical signs we found that there was good clinical response and pro- of leishmaniosis should be treated [8–10]. No statisti- longed survival in many cats given allopurinol as a mono- cally significant difference in survival time was found therapy at 10 mg/kg PO BID for at least 6 months. between treatment with allopurinol as monotherapy and allopurinol in combination with other drugs. This Abbreviations suggests that monotherapy with allopurinol could be CanL: Canine leishmaniosis; DSH: Domestic short haired; FeL: Feline leishmani‑ osis; FIV: Feline immunodeficiency virus; IFAT: Indirect fluorescent antibody used as a first line treatment in cats for at least for technique; PCR: Polymerase chain reaction. 6 months, and for those cats not responding to treat- ment with allopurinol alone, meglumine antimoniate Acknowledgements This paper is sponsored by Elanco Animal Health in the framework of the 16 could be added to try and further improve the clinical Companion Animal Vector-Borne Diseases (CVBD) World Forum Symposium. signs of leishmaniosis. However, caution is warranted because the effects of specific leishmaniosis treatments Author contributions MGT, MCL, CB and XR designed and developed the study. MGT and MCL on survival could not be assessed here due to the great collected and processed the database data. MGT and XR wrote the manu‑ variability in the dosages of the different drugs used, script. ST, MCL, MRL and CB revised the manuscript. All the authors read and and because the type, quality and intensity of support- approved the final manuscript. ive treatments used for each of the cats included in this Author information study were unknown. No other statistically significant ST, MRL and XR are members of the CVBD World Forum, which is supported association was found between survival time and any by Elanco Animal Health. other variable such as age, breed, sex, indoor/outdoor Funding access, comorbidities, clinical signs or clinicopatho- Not applicable. logical abnormalities, diagnostic test results and type of Availability of data and materials treatment, and thus no potential predictive factors for Not applicable. Garcia‑Torres et al. Parasites & Vectors (2022) 15:253 Page 11 of 13 Declarations 17. Bosselut H. Un cas de leishmaniose générale du chat. 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Lopez M, Aybar V, Zatelli A, Vila A, Vega J, Hernando E, et al. Is proteinu‑ • support for research data, including large and complex data types ria a rare condition in apparently healthy and sick cats? a feline practice experience (2007–2018). Open Vet J. 2021;11:508–16. • gold Open Access which fosters wider collaboration and increased citations 102. Brianti E, Falsone L, Napoli E, Gaglio G, Giannetto S, Pennisi MG, et al. • maximum visibility for your research: over 100M website views per year Prevention of feline leishmaniosis with an imidacloprid 10%/flumethrin 4.5% polymer matrix collar. Parasit Vectors. 2017;10:334. At BMC, research is always in progress. 103. Benassi JC, Benvenga GU, Ferreira HL, Pereira VF, Keid LB, Soares R, et al. Detection of Leishmania infantum DNA in conjunctival swabs of cats by Learn more biomedcentral.com/submissions quantitative real-time PCR. Exp Parasitol. 2017;177:93–7.