216_228_Murillo2.qxp_FAB 03/02/2020 12:44 Page 216 Journal­of­Feline­Medicine­and­Surgery (2020) 22, 216–228 CLINICAL REVIEW LEPTOSPIROSIS IN CATS Current literature review to guide diagnosis and management Global importance: Leptospirosis is the most widespread zoonosis worldwide. Mammals (eg, rats, horses, cows, pigs, dogs, cats and aquatic species, such as sea lions and northern elephant seals) can all be infected by leptospires. Infection in animals occurs through contact with urine or water contaminated with the bacteria. In people, the disease is acquired mainly from animal sources or through recreational activities in contaminated water. Andrea Murillo1 Practical relevance: Literature on the clinical presentation of leptospirosis in cats is scarce, MV, MSc although it has been demonstrated that cats are susceptible to infection and are capable of Marga Goris2 MSc, PhD developing antibodies. The prevalence of antileptospiral antibodies in cats varies from 4% to 33.3% Ahmed Ahmed2 depending on the geographical location. Urinary shedding of leptospires in naturally infected cats has MV, MSc, PhD been reported, with a prevalence of up to 68%. Infection in cats has been associated with the consumption Rafaela Cuenca1* of infected prey, especially rodents. Thus, outdoor cats have a higher risk of becoming infected. MV, MSc, PhD Clinical challenges: Clinical presentation of this disease in cats is rare and it is not known what role cats Josep Pastor1 have in the transmission of leptospirosis. Ongoing work is needed to characterise feline leptospirosis. MV, MSc, PhD, Dip ECVCP Audience: This review is aimed at all veterinarians, both general practitioners who deal with cats on a daily 1 Departament de Medicina basis in private practice, as well as feline practitioners, since both groups face the challenge of diagnosing i Cirurgia Animals, and treating infectious and zoonotic diseases. Facultat de Veterinària, Universitat Autònoma Evidence base: The current literature on leptospirosis in cats is reviewed. To date, few case reports have de Barcelona, been published in the field, and information has mostly been extrapolated from infections in people and 08193 Bellaterra, dogs. This review is expected to serve as a guide for the diagnosis and management of the disease in cats. Cerdanyola del Vallès, Barcelona, Spain Keywords: Leptospirosis; microscopic agglutination test; real-time PCR; zoonosis 2 OIE and National Collaborating Centre for Reference and Research on Leptospirosis (NRL), Aetiology each with distinct antigenic compositions; to Amsterdam UMC, date, over 260 pathogenic serovars, arranged University of Amsterdam, Medical Microbiology, Leptospirosis is caused by spirochetal bacteria into 26 serogroups, have been identified. This Meibergdreef 39, of the genus Leptospira. These are highly serological classification, based on determin- 1105 AZ, Amsterdam, motile, elongated and helically coiled bac- ing antigenic characteristics, is more useful Netherlands teria that differ morphologically from other diagnostically and also better serves epidemi- *Corresponding author: spirochetes by having a ‘question mark’ or ological purposes. rafaela.cuenca@uab.cat hook-shaped end.1–3 The genus Leptospira All mammals may be susceptible to Lepto­- was originally divided into two species: spira­infection.3 There are primary (definitive) Leptospira­ interrogans, containing the patho- or carrier hosts for some serovars (eg, dogs genic serovars, and Lepto­spira­biflexa, contain- are hosts for Canicola; cows and sheep for ing the non-pathogenic saprophytic serovars.4 Hardjo; pigs for Pomona and Bratislava; However, this phenotypic classification has and rats for Icterohaemorrhagiae and Copen- been largely superseded by genetic classi- hageni). These contribute to a greater extent to fication, based on genotypic identification the spread of bacteria in the environment techniques, that includes all serovars of compared with incidental or dead-end hosts L­interrogans­sensu lato and L­biflexa­sensu lato (ie, that suffer acute disease and are unlikely (sensu lato is a Latin phrase meaning ‘in the to serve as a source of transmission; eg, broad sense’ and is often used taxonomically humans). The definitive host is typically infect- to indicate a species complex).3 ed at a young age and commonly exhibits Currently, 22 species of Leptospira have minimal clinical disease, whereas animals been identified;4 at least 10 of these are infected with non-host-adapted serovars are pathogenic. There are also seven saprophytic expected to exhibit more severe clinical signs.3 species and five species of indeterminate pathogenicity.5 It is likely that more species will be described in the future. Pathogenic Leptospira species are divided into serovars, 216 JFMS CLINICAL PRACTICE DOI: 10.1177/1098612X20903601 © The Author(s) 2020 216_228_Murillo2.qxp_FAB 03/02/2020 12:44 Page 217 R E V I E W / Leptospirosis in cats Outdoor cats have an increased risk of leptospirosis, through contact with reservoir hosts. Figure 1 Map indicating (in red) the countries where the prevalence of leptospirosis in cats has been reported, based on microscopic agglutination test (MAT) and/or urinary and blood PCR Epidemiology lence of leptospirosis in cats has been report- At present, it is ed, based on MAT and/or urinary and Leptospirosis is endemic in almost all regions blood PCR. Table 1 summarises previous of the world.2 Its incidence usually increases not completely research on feline leptospirosis prevalence at the end of the summer months, while understood by MAT diagnosis. Overall seropositivity in the tropics most infections occur during reported in these studies ranged from 4% and after periods of rainfall.1,2 Pathogenic which serovars to 33.3%, with no clear association with clini- Leptospira­ species experience optimal growth cal disease. at temperatures of 28–30ºC. Although they do cause Leptospiral infection in cats has been associ- not replicate outside of the host, they can sur- incidental ated with the consumption of infected prey,29 vive for months in moist soil saturated with involving serovars of the Autumnalis and urine,1,3 and this can lead to significant envi- infections in Ballum serogroups.3 Outdoor cats have an ronmental contamination. In people, there cats and which increased risk of becoming infected with lep- are three main factors associated with the risk tospires since they are in close contact with of disease transmission: (1) water exposure; have developed reservoir hosts. In rural areas, cats can also (2) exposure to carrier rodents; and (3) trans- become infected via urine from pigs and mission from livestock or pets.6 adaptation to cows.12,15,28–30 The presence of another cat in Feline leptospirosis was first described in feline species. the household significantly increases the risk 1972,7 and prevalence studies show the main of seropositivity for leptospirosis.14 serovars belong to serogroups Australis, At present, it is not completely understood Autumnalis, Canicola and Sejroe,8–18 although which serovars cause incidental infections there are geographical variations. The most in cats. Based on previously published frequent serovars involved in feline lepto- reports of acute leptospirosis in cats, serovars spirosis in Europe – according to the European belonging to Autumnalis, Australis, Ictero- consensus statement on leptospirosis, and haemorrhagiae, Grippotyphosa, Pomona based on the prevalence of antibodies mea- and Sejroe serogroups are involved.14,18,30–32 sured by the microscopic agglutination test Several studies have confirmed renal carriage (MAT) – belong to serogroups Australis, of Leptospira species by PCR, and these Autumnalis, Ballum, Canicola, Grippotyphosa, cats had antibodies mainly against serovars Icterohaemorrhagiae, Pomona and Sejroe.19 belonging to Australis, Canicola, Ictero- The most commonly reported serovars in cats haemorrhagiae and Pomona serogroups. in the USA belong to serogroups Australis, Given this fact, cats could be a chronic reser- Autumnalis, Grippotyphosa and Pomona.8,20 voir host for the bacteria and a possible risk Figure 1 shows the countries where the preva- factor for human infection.10,11,13,14,16,26,30,33,34 JFMS CLINICAL PRACTICE 217 216_228_Murillo2.qxp_FAB 03/02/2020 12:44 Page 218 R E V I E W / Leptospirosis in cats Table 1 Prevalence data for leptospirosis in cats diagnosed by microscopic agglutination test Location n Positive serovar(s) Negative serovar(s) Prevalence (%) Reference Malaysia – Johor and 110 Ballum, Bataviae*, Australis, Autumnalis, Canicola, Celledoni, Cynopteri, 18.1 9 Selangor Copenhageni and Javanica Djasiman, Grippotyphosa, Hardjo, Hardjo-bovis, Hebdomadis, Icterohaemorrhagiae, Lai, Malaysia, Pomona, Pyrogenes and Tarassovi Thailand – 13 locations 260 Anhoa, Autumnalis, Celledoni, Australis, Ballum, Bataviae, Bratislava, Broomi, 5.4 10 Copenhageni, Djasiman, Canicola, Coxi, Cynopteri, Grippotyphosa, Icterohaemorrhagiae Haemolytica, Khorat, Paidjan, Pomona, Pyrogenes, and Patoc* Rachmati, Saxkoebing and Sejroe USA – Iowa 139 Bratislava*, Grippotyphosa, Canicola 8.6 8 Hardjo, Icterohaemorrhagiae and Pomona Germany – Munich 215 Australis*, Autumnalis, Canicola, Pomona and Saxkoebing 17.9 11 Bratislava, Copenhageni and Grippotyphosa Caribbean island 50 Cynopteri and Pomona Alexi, Australis, Autumnalis, Bataviae, Ballum, 4 21 of St Kitts Borincana, Bratislava, Canicola, Celledoni, Cynopteri, Djasiman, Georgia, Grippotyphosa, Hardjo, Icterhemorrhagiae, Javanica, Mankarso, Pomona, Pyrogenes, Tarassovi and Wolffi Brazil – Lago Grande 43 Andamana and Patoc Autumnalis, Australis, Bataviae, Bratislava, Butembo, 4.7 22 Canicola, Castellonis, Copenhageni, Cynopteri, Grippotyphosa, Guaricura, Hardjo-prajitno, Hebdomadis, Icterohaemorrhagiae, Javanica, Panama, Pomona, Pyrogenes, Shermani, Tarassovi, Whitcombi and Wolffi Mexico – Mérida 13 Australis and Canicola* Autumnalis, Bratislava, Grippotyphosa, Hardjo, 23.2 23 Icterohaemorrhagiae, Pyrogenes, Panama, Pomona, Tarassovi and Wolffi Iran – Mashhad 147 Hardjo*, Icterohaemorrhagiae Autumnalis, Ballum, Canicola and Grippotyphosa 12.9 12 and Pomona Taiwan – Southern 225 Australis, Autumnalis, Bataviae, Canicola, Panama, Pomona 9.3 13 Taiwan Icterohaemorrhagiae, and Tarassovi Javanica, Pyrogenes and Shermani* Canada – Quebec 240 Bratislava, Grippotyphosa, Canicola and Hardjo 10.8 14 Icterohaemorrhagiae and Pomona* Chile – Valdivia, 124 Autumnalis*, Bataviae Ballum, Hardjo, Icterohaemorrhagiae and Pomona 25.2 15 Osorno, Paillaco and Canicola and San Pablo Serbia – Belgrade 161 Australis*, Bratislava, Autumnalis, Bataviae, Icterohaemorrhagiae 26.7 24 Canicola, Grippotyphosa and Sejroe Pomona* and Pyrogenes Canada – Quebec 40 Autumnalis and Bratislava* Canicola, Grippotyphosa, Icterohaemorrhagiae 25 25 and Pomona Reunion Island 30 Panama Australis, Autumnalis, Bataviae, Canicola, 26.6 26 Castellonis, Cynopteri, Grippotyphosa, Hardjo-bovis, Hebdomadis, Icterohaemorrhagiae, Copenhageni, Pomona, Pyrogenes, Sejroe and Tarassovi Iran – Ahvaz 102 Australis and Ballum* Canicola, Grippotyphosa, Hardjo, 4.9 27 Icterohaemorrhagiae and Pomona USA – Massachusetts 63 Autumnalis*, Bratislava, Canicola, Grippotyphosa and Hardjo 4.8 20 Icterohaemorrhagiae and Pomona Spain – Andalucia 53 Ballum and Australis, Autumnalis, Bataviae, Bratislava, Canicola, 14 16 Icterohaemorrhagiae* Grippotyphosa, Hardjo, Hebdomadis, Pomona, Saxkoebing, Sejroe and Tarassovi Greece – Thessaloniki 99 Ballum, Bataviae, Bratislava, Hebdomadis, Panama and Pomona 33.3 17 Canicola, Panama, Pyrogenes and Rachmati* Scotland – Glasgow 87 Autumnalis, Hardjo-bovis* Autumnalis, Bratislava, Ballum, Canicola, Cynopteri, 9.2 18 and Icterohaemorrhagiae Grippotyphosa, Javanica, Pomona and Tarassovi New Zealand – North 225 Balcanica, Ballum, Canicola, Australis, Bataviae, Javanica, Pyrogenes and 8.8 28 Island Copenhageni*, Hardjo* and Tarassovi Pomona *Most prevalent serovar reported in the study 218 JFMS CLINICAL PRACTICE 216_228_Murillo2.qxp_FAB 03/02/2020 12:44 Page 219 R E V I E W / Leptospirosis in cats Table 2 summarises the scant research that has Summary of current research on prevalence of urinary Table 2 been carried out in cats in different countries shedding of Leptospira DNA in cats to determine the prevalence of Leptospira DNA shedding in urine. In these studies, Location n Gene target/primer set Prevalence (%) Reference the prevalence ranged from 0% to 67.8%, Reunion Island 172 rrs2, lipL32 and lipL41 0.6 35 with no clear association with clinical disease. The prevalence may differ depending on the Thailand – 13 260 lipL32 0.8 10 locations geographical location and the PCR-selected primers, among other factors. Algeria – Algiers 107 rrs (16S) and hsp 0 36 Germany – 215 lipL32 3.30 11 Pathogenesis Munich Australia – 59 23S 42.4 33 Depending on the host and infecting serovar, Christmas Island leptospiral infection may cause a spectrum of Canada – 240 G1 and G2 and 3.33 14 syndromes from asymptomatic carriage to Quebec B64-I/B64-II fulminant, acute disease.3 Reports of clinical disease due to Leptospira species in pet cats are Réunion Island 30 lipL32 26.6 26 scarce. Taiwan – 225 G1/G2 and Leptospira rrs 67.8 13 Leptospires can enter the body through cuts Southern Taiwan (16S) and abrasions, mucous membranes, such as the conjunctiva, or through moist, weakened skin. The bacteraemia lasts around 7 days. The pathogenesis of the disease in cats Cats can act as carrier hosts, remains unknown, although it is assumed not developing clinical disease, but shedding to be similar to that in humans and dogs37 (Figure 2). Acute clinical disease occurs with bacteria into the environment in their urine. the bacteraemic phase of the disease.1,2,38 It is seen mainly in young incidental hosts and is usually associated with haemolysin- The duration of elimination via the urine producing bacteria, such as the Ictero- and its intensity varies from species to species haemorrhagiae or Pomona serogroups, which and animal to animal, and depends on the cause haemolytic disease, haemoglobinuria, infecting serovar;3 precise information on jaundice and, in severe cases, death.3 After these aspects is currently unavailable in cats. leptospires have reached a critical level in the As mentioned earlier, cats can act as blood, clinical signs appear due to the action carrier hosts, not developing clinical disease, of leptospiral toxins or toxic cellular compo- but shedding bacteria into the environment nents.1,2,38 Organ damage occurs as a result of in their urine. An epidemiological study leptospires replicating and inducing cytokine has confirmed the presence of leptospiral production and by direct invasion of inflam- DNA in the urine of cats for more than matory cells.3 8 months after infection, with little or no The primary lesions develop in the endo- association with disease.11 However, this does thelium of the small blood vessels, leading not rule out the possibility that infected to localised ischaemia, and resulting in animals could develop kidney disease at a renal tubular necrosis, among other target later stage. The development of the carrier organ damage (Figure 2). Renal colonisation state and the specific mechanisms required for occurs in most infected animals because leptospires to enter the lumen of the proximal the bacteria replicate and persist in the cells renal tubules, adhere to renal epithelial cells, of the renal tubule epithelium. This multi- evade antibodies in the filtrate and acquire plication process causes the release of the nutrients they need to replicate are not cytokines and the recruitment of inflam- well understood.3 matory cells, which trigger nephritis.1,2,38 Leptospiral pulmonary haemorrhage syn- Chronic interstitial nephritis, which may drome (LPHS) has been recognised in people result in chronic renal damage, has been and dogs. This syndrome may be present described in cats infected with leptospires.16 in 70% of dogs infected with leptospires.39 After 10 days of infection, leptospires enter The clinical signs associated with canine the tubular lumen and are eliminated in LPHS are mainly acute and findings corre- the urine over a period of days to months.1,2,38 spond to severe alveolar and subpleural Although the pathogenesis of feline leptospirosis is not yet well understood, it is assumed to be very similar to that in humans and dogs. JFMS CLINICAL PRACTICE 219 216_228_Murillo2.qxp_FAB 03/02/2020 12:44 Page 220 R E V I E W / Leptospirosis in cats The presence of another cat in the household significantly increases the risk of seropositivity for leptospirosis. Figure 2 Proposed pathogenesis of leptospirosis in cats. The figure depicts the transmission mechanisms through which a cat can become infected by Leptospira species: preying on rodents, sharing the environment with farm animals that shed the bacteria in urine, or through standing water containing bacteria. Once the animal has become infected it suffers a period of bacteraemia of approximately 7 days and leptospires can be identified in blood. The main target organs in cats are the kidney and the liver; lungs, brain and eyes may also be affected, especially in dogs. Replication of leptospires occurs in the kidney leading to urinary bacterial shedding. Image ©Biorender haemorrhages, which cause an associated necrosis have been reported.14,16,31 Damage to dyspnoea. While, to date, LPHS has not been organs including the spleen, eyes, meninges, described in cats, chronic liver inflammatory muscle and placenta has also been reported in infiltration, fibrosis and multifocal hepatic species other than cats.2,3,40 Virulence mechanisms and host factors The virulence mechanisms of leptospires and the cytokines and chemokines is more prolific in intrinsic factors of the host that determine the animal species susceptible to severe leptospirosis result of infection remain poorly understood. compared with resistant animal species.49 Recent mutagenesis studies in animal models of Pathogenic leptospires are resistant to the bacte- acute infection and of renal colonisation have ricidal activity of complement, while saprophytic demonstrated that specific genes and proteins, leptospires are highly susceptible.41,50,51 The abili- among them lipoproteins LipL32 and LipL41 and ty to acquire iron in vivo is a key virulence property LigB adhesin, are present in pathogenic Leptospira for most bacterial species. Pathogenic leptospires species, but are not necessary for virulence.3,41,42 possess haemoxygenase (HemO), which facili- Loa22, an outer membrane protein containing a tates the acquisition of iron from heme, the C-terminal OmpA domain, plays an indirect role major source of iron in the mammalian host.52,53 in the virulence of Leptospira species.43 Changes However, no conclusive results were obtained in in motility through modifications in or mutations relation to attenuation of virulence of leptospires of genes involved in flagellar structure also play a in a study using a HemO mutant.54 role in the specific virulence of leptospires.44,45 Mutagenesis studies have also demonstrated Adhesion to host tissues appears to be a pre- that several stress response genes, which are requisite for successful infection; however, genet- upregulated with bacterial transition from the ic studies have not confirmed a definitive role for environment to the host, increase their suscepti- many adhesins in the pathogenesis of Leptospira bility to oxidative stress and therefore render species.3 With regard to the survival of leptospires the bacteria less virulent.55–57 In the same way, in vivo, it has been suggested that pathogenic the inactivation of Mce, a homologue of the leptospires undergo receptor-mediated endo- mycobacterial mammalian cell entry protein in cytosis46,47 and are able to survive inside leptospires, has been found to result in a signifi- macrophages.48 Production of pro-inflammatory cant reduction in virulence.58 220 JFMS CLINICAL PRACTICE 216_228_Murillo2.qxp_FAB 03/02/2020 12:44 Page 221 R E V I E W / Leptospirosis in cats Table 3 Clinical signs of leptospirosis in cats based on published studies of acute disease Reference Serovar(s) Clinical signs Diagnosis MAT PCR 11 Australis Seizures Not reported + + Prospective 11 Australis, Bratislava and Copenhageni Acute diarrhoea Not reported + + study 14 Bratislava, Grippotyphosa, Icterohaemorrhagiae Not reported AKI 4+ NP and Pomona 18 Autumnalis, Hardjo, and Icterohaemorrhagiae Not reported AKI 8+ NP 32 Saxkoebing Vomiting and diarrhoea, hyperaesthesia AKI – + + and painful on handling leptospirosis Case report 31 Grippotyphosa, Hardjo, Icterohaemorrhagiae Polyuria and polydipsia AKI – + NP and Pomona leptospirosis 31 Bratislava, Grippotyphosa and Pomona Polyuria, polydipsia, haematuria and lameness AKI – + NP leptospirosis 31 Autumnalis, Bratislava, Grippotyphosa Comatose AKI – + + and Pomona leptospirosis 30 Autumnalis and Pomona Haematuria Leptospirosis + + MAT = microscopic agglutination test; + = positive; – = negative; AKI = acute kidney injury; NP = not performed; 4+, 8+ = number of positive cats in the study Clinical signs in Diagnosis with antibodies against Leptospira species have been found to have signs associated with renal cats are mild or Clinical signs disease and/or histopathological evidence absent despite In cats, clinical signs are, at most, mild, of renal inflammation.14,16,30,35,59 As in dogs, despite the presence of leptospires in the leptospirosis in cats can cause acute kidney the presence blood and urine. injury that leads to chronic kidney disease.19,60 of leptospires Clinical signs reported in infected cats Lesions in the liver of affected cats have been (based on confirmation by MAT and/or PCR) reported less commonly than in dogs.11,18,29,31,32 in the blood include polyuria, polydipsia, haematuria, Tables 3–5 collate information from several uveitis, lameness, lethargy, anorexia, weight papers that detail the clinical signs in cats and urine. loss, ascites, vomiting, diarrhoea, pain on han- at the time of presentation, the laboratory dling, and inflammatory lesions on the skin test used for diagnosis and the Lepto­­spira­ and digits.11,14,17,18,25,30–32,59 Pathological find- serovars­involved. The cases have been divid- ings reported in these animals include the ed into cats with acute disease (Table 3), those presence of haemorrhagic or straw-coloured identified as chronic carriers (Table 4) and thoracic and peritoneal fluids.31,18 Some cats those with a history of exposure (Table 5). Table 4 Clinical signs of leptospirosis in cats according to published studies of chronic carrier cases Reference Serovar(s) Clinical signs Diagnosis MAT PCR 11 Australis and Bratislava Asymptomatic Incidental infection (routine + + health check) 11 Grippotyphosa Not reported Mast cell tumour in spleen and liver + + 11 Not determined Not reported Foreign body in pharynx (grass) – + Prospective study 11 Grippotyphosa Not reported CKD and abdominal mass + + 11 Australis, Autumnalis, Bratislava Chronic diarrhoea Not reported + + and Copenhageni 14 Bratislava, Copenhageni, Not reported CKD 13+ 6+ Grippotyphosa and Pomona 14 Bratislava, Grippotyphosa, Not reported Incidental infection (routine 9+ 2+ Icterohaemorrhagiae and health check) Pomona 16 Icterohaemorrhagiae Kidney: Chronic interstitial nephritis. Not reported + NP Chronic inflammatory infiltrate (macrophages and lymphocytes) Liver: Chronic inflammatory infiltration 16 Canicola Asymptomatic Not reported + NP MAT = microscopic agglutination test; + = positive; – = negative; CKD = chronic kidney disease; NP = not performed; 13+, 6+, etc = number of positive cats in the study JFMS CLINICAL PRACTICE 221 216_228_Murillo2.qxp_FAB 03/02/2020 12:44 Page 222 R E V I E W / Leptospirosis in cats Table 5 Clinical signs of leptospirosis in cats based on published studies of animals with a history of exposure Reference Serovar(s) Clinical signs Diagnosis MAT PCR 9 Ballum, Bataviae and Javanica Not reported Feline upper + NP respiratory disease 15 Autumnalis, Bataviae, Canicola Asymptomatic Incidental infection 10+ NP and Grippotyphosa (routine health check) 24 Australis, Bataviae, Bratislava, Asymptomatic Incidental infection 43+ NP Canicola, Grippotyphosa, (neutering) Icterohaemorrhagiae, Pyrogenes, Pomona and Sejroe 25 Autumnalis and Bratislava Not reported CKD + NP 25 Autumnalis and Bratislava Polyuria and polydipsia Not reported + NP Prospective study 25 Autumnalis and Bratislava Not reported Hepatic lipidosis 2+ NP 25 Autumnalis and Bratislava Asymptomatic Not reported 3+ NP 27 Australis and Ballum Asymptomatic Not reported 5+ NP 16 Icterohaemorrhagiae Kidney: Chronic interstitial nephritis. Chronic Not reported + NP inflammatory infiltrate (macrophages, lymphocytes and plasma cells). Proliferative glomerulonephritis Liver: Multifocal hepatic necrosis. Chronic inflammatory infiltrate (lymphocytes and plasma cells) 16 Ballum Kidney: Chronic interstitial nephritis. Chronic Not reported + NP inflammatory infiltrate (macrophages and plasma cells) 16 Ballum Asymptomatic Not reported + NP 16 Icterohaemorrhagiae Kidney: Chronic interstitial nephritis. Chronic Not reported + NP inflammatory infiltrate (macrophages and lymphocytes) 17 Rachmati Asymptomatic Not reported 15+ NP 17 Rachmati Not reported Various chronic 18+ NP diseases Retrospective 59 Bratislava and Not reported CKD – azotaemia 4+ NP Icterohaemorrhagiae study 59 Bratislava and Not reported CKD – non-azotaemia 8+ NP Icterohaemorrhagiae MAT = microscopic agglutination test; + = positive; – = negative; CKD = chronic kidney disease; NP = not performed; 10+, 43+, etc = number of positive cats in the study Polyuria, polydipsia, haematuria, uveitis, laminitis, lethargy, anorexia, weight loss, vomiting and diarrhoea, painful handling, and inflammatory lesions on skin and foot digits are some of the clinical signs reported in affected cats. Clinicopathological data with azotaemia at the time of diagnosis. Table 6 summarises some of the most common The increase is usually moderate to sev- clinicopathological abnormalities associated ere.11,14,25,31,32,59 In affected dogs, serum liver with leptospirosis in cats. enzyme (alkaline phosphatase [ALP] more commonly than alanine aminotransferase Complete blood count [ALT]) and total bilirubin increases are associ- Leukocytes can fluctuate according to the ated with liver dysfunction.38,40,60 Conversely, stage and severity of infection. Leukopenia is in feline leptospirosis these increments are a possibility during leptospiraemia, evolving not as characteristic, and only slight increases to leukocytosis owing to neutrophilia with a have been reported.11,18,25,31,32 Leptospire tox- left shift. In advanced states, leukocyte counts ins inhibit Na+K+-ATPase activity in the may be in the range of 16.5–45 x 109/l (refer- epithelial cells of the renal tubules in cats and ence interval 2.75–11.75 x 109/l).18,19,60,61 dogs, which can lead to significant renal losses of electrolytes, resulting in severe hypo- Serum biochemistry kalaemia.60 In cats, increases in serum phos- Urea and creatinine concentrations are phorus concentration have been reported, increased in 80–90% of cases of canine probably associated with a decrease in the leptospirosis.60 Most infected cats present glomerular filtration rate.31 222 JFMS CLINICAL PRACTICE 216_228_Murillo2.qxp_FAB 03/02/2020 12:44 Page 223 R E V I E W / Leptospirosis in cats Urine analysis Table 6 Clinicopathological findings in 19 cats diagnosed Findings in dogs include isosthenuria or occa- with leptospirosis11,18,30–32 sionally hyposthenuria, glycosuria, protein- uria, bilirubinuria, haematuria, pyuria and the Affected/sampled Finding Clinical course cats presence of casts in fresh urine sediment.38,60 In cats, hyposthenuria, haematuria and pro- Haematology Non-regenerative Chronic carrier 2/19 (10.5%) anaemia teinuria have been reported.30,31 Leptospires are not visible on routine fresh urinary sedi- Haemoconcentration Acute disease 2/19 (10.5%) ment examination, as the size of the bacteria is Neutropenia Acute disease 1/19 (5.2%) below the resolution of light microscopy.19 Neutrophilia Acute disease 2/19 (10.5%) Leukocytosis with Acute disease 2/19 (10.5%) Ultrasonographic findings left shift The few published reports of feline lepto- Thrombocytopenia Acute disease 1/19 (5.2%) spirosis describe renal ultrasonographic Biochemistry Hypoalbuminaemia Acute disease 2/2 (100%) findings that are similar to those in canine Azotaemia Acute disease and 9/19 (47.4%) leptospirosis, including a granular appear- chronic carrier ance of the kidney, enlarged kidneys with Liver enzymes increased Acute disease 6/8 (75%) a cortex that is thinner than the medulla, Hyperglycaemia Acute disease 1/2 (50%) a slightly hyperechogenic renal cortex and Hyperphosphataemia Acute disease 1/1 (100%) a decrease in the definition of the corti- Bicarbonate decreased Acute disease 1/1 (100%) comedullary junction.31,32 Heterogeneity in the pancreatic and liver parenchyma has also Urine analysis Low USG Acute disease and 3/5 (60%) chronic carrier been reported in one case.32 Proteinuria Acute disease 3/6 (50%) Specific testing Haematuria Acute disease 2/6 (33.3%) Laboratory diagnosis of leptospirosis in veteri- Renal and red cell casts Acute disease 1/5 (20%) nary medicine is usually based on the demon- Serological FeLV/FIV negative Acute disease 5/5 (100%) stration of serum antibodies by MAT and test ELISA, and/or isolation of Leptospira­ DNA USG = urine specific gravity; FeLV = feline leukaemia virus; FIV = feline from blood and urine by PCR. Bacterial cul- immunodeficiency virus ture of blood and/or urine is not widely used because it is time consuming. Specific diag- Several studies have confirmed renal nostic tests that are available for cats are MAT and PCR. carriage of Leptospira species in cat Microscopic agglutination test populations, which means cats could be a Determination of antibody titre by MAT is chronic reservoir host for the bacteria and a the recommended technique for leptospirosis diagnosis, as MAT reactivity to a serovar sug- possible risk factor for human infection. gests exposure to a serovar belonging to the corresponding serogroup (though not neces- MAT results are strongly dependent on labo- sarily to the specific serovar tested).62 The selec- ratory quality control, and there is considerable tion of the serogroups and the serovars to be inter-laboratory variability.63 Practitioners are evaluated depends on the geographical loca- encouraged to submit diagnostic samples to tion of the patient’s likely exposure. Antibodies laboratories that adhere to a proficiency (IgM and IgG) are detected at around 15 days scheme.64 Test interpretation may be more reli- post-infection by MAT.3 Little information is able in cats than in dogs because no interfer- available on the duration of these antibodies ence with vaccine antibodies exists as cats in the blood of cats. Clinical interpretation are not vaccinated.37 Furthermore, laboratory- should always be based on the results of paired reared young adult specific pathogen-free cats serum titres, and it is worth noting that some infected with Borrelia­ burgdorferi did not form infected animals may produce a result that is antibodies against Leptospira­species as a cross- lower than the widely accepted minimum sig- reaction.59 The authors of that study suggest nificant titre result of 1:100.3 It is even possible that positive Leptospira­ species MAT results that seroconversion in cats is expressed at a from cats in the field are likely to reflect anti- lower titre compared with dogs.59 bodies against leptospires and not B­burgdorferi. MAT results are strongly dependent on quality control procedures in the laboratory. Practitioners are encouraged to submit diagnostic samples to laboratories that adhere to a proficiency scheme. JFMS CLINICAL PRACTICE 223 216_228_Murillo2.qxp_FAB 03/02/2020 12:44 Page 224 R E V I E W / Leptospirosis in cats ELISA and rapid immunodiagnostic PCR screening tests PCR directly identifies leptospiral DNA. It ELISAs used for leptospirosis identify the pres- ELISA does not determine the infecting serogroup ence of leptospiral antibodies (specific IgM class or serovar, but it can indicate the Leptospira antibodies) earlier than MAT, at between 4–6 days and rapid species. The test can be performed on blood, post-infection.3 The main advantages of ELISA patient-side urine, cerebrospinal fluid and body tissues. compared with MAT are, in the authors’ opin- In cases of acute leptospirosis, this would be ion, the stability of antigenic preparations and tests for the test of choice to perform on blood and the genus specificity, meaning all types of lep- urine in cats. Compared with culture, PCR tospires can be diagnosed with a single antigenic Leptospira gives fast results, contributing to an early preparation, irrespective of the causal serovar.65 species diagnosis.65 Real-time PCR techniques are rec- In dogs, a combination of ELISA plus MAT is ommended, due to their greater sensitivity recommended for leptospirosis diagnosis.19 diagnosis in and specificity. Genes that have more than Rapid patient-side tests for leptospirosis diag- one copy in the genome, such as lig or rrs,­ nosis were developed almost a decade ago.66 cats have not should be selected with the aim of increasing Curtis et al performed a recombinant LipL32- yet been the sensitivity of the technique. Genes present based rapid in-clinic ELISA (SNAP Lepto) for only in the pathogenic species can also be the detection of antibodies against Leptospira­ developed. added as they will increase the specificity of species­ in dogs in 2015.67 Neither of the tests the test.68 distinguish between serovars, nor do they pro- A positive PCR result means that leptospiral vide a titre magnitude. The first test66 is based DNA is present in the sample. In acute on the detection of Leptospira-specific IgM and infections or in chronic carriers, the test has demonstrated a sensitivity and specificity would be positive in urine, indicating that of 100% and 95.3%, respectively. It can there- bacterial DNA is being shed. However, fore detect dogs with clinically suspected acute negative results in blood and urine do not leptospirosis. Dogs previously vaccinated or suf- rule out leptospirosis, as leptospiraemia is fering from an acute but subclinical infection can transient (only occuring in the initial phases also produce positive results. A LipL32-based in- of the disease); also results are usually clinic ELISA for the rapid detection of Leptospira- negative if the cat has received antibiotic specific antibodies in dogs is not IgM specific, therapy,19,60 and shedding in urine can be but the study authors considered it a convenient intermittent.3 In one report, leptospires were tool to assess Leptospira antibody status in dogs.67 cultured from cat urine and the results were Neither rapid test techniques, nor ELISA, to confirmed by PCR,34 suggesting that cats diagnose leptospirosis in cats have yet been can shed living Leptospira­ bacteria, not just developed. their DNA. Diagnostic approach for a cat with suspected leptospirosis Supportive therapy with intravenous ampicillin while the LEPTOSPIROSIS patient is stabilised. Doxycyline LEPTOSPIROSIS oral suspenion for 6 weeks. POSITIVE Then perform real-time PCR on History of exposure, urine to rule out carrier status YES and clinical findings and clinicopathological Real-time PCR on abnormalities YES Perform MAT Antibodies, paired blood and urine consistent with samples (2 weeks apart), leptospirosis seroconversion Blood 1. Antimicrobial therapy prior to sampling and/or NO 2. Sampling after leptospiraemia (>7 days) NEGATIVE Urine Rule out 1. Antimicrobial therapy prior to sampling NO leptospirosis and/or 2. Sampling before leptospiruria (<10 days) and/or 3. Intermittent Leptospira DNA shedding (>10 days) MAT = microscopic agglutination test 224 JFMS CLINICAL PRACTICE 216_228_Murillo2.qxp_FAB 03/02/2020 12:44 Page 225 R E V I E W / Leptospirosis in cats Treatment Prognosis The prognosis depends principally on the severity of any organ damage. Supportive therapy In dogs that develop LPHS, the prognosis is usually poor since the animal is Intravenous fluids should be given to in acute respiratory failure with associated dyspnoea resulting from damage affected animals to correct the electrolyte to the small pulmonary vessels, as described earlier; LPHS is one of the most fluid imbalance. The use of centrally acting common leptospiral-associated causes of death in dogs. The prognosis antiemetics and the parenteral administration is also poor for affected animals that develop acute renal injury unless of gastric protectors is recommended in cats haemodialysis is available.60 that develop associated renal failure. Pain In cats with mild clinical signs and no severe organ damage, response to management is particularly important in the specific antimicrobial therapy and outcome are good.30–32 Cats that survive early stages of the disease to treat painful acute renal failure, and especially those treated in the chronic phase of swollen kidneys, muscle, joints and gastro- leptospirosis, may develop renal damage as a consequence of the initial intestinal tissue.19 condition, and this may be permanent. Case notes A 2-year-old intact male domestic shorthair cat, showing lethargy and anorexia for 5 days, was Clinical pathology results presented for investigation. Complete blood count Case work-up The cat Result RI was an indoor–outdoor RBCs (x 1012/l) 6.2 6–10.2 animal with a history of Hb (g/dl) 10.5 9–15 hunting small rodents. HCT (l/l) 0.3 0.3–0.5 Vaccinations were current. MCV (fl) 47.2 41–53 On admission, the cat was MCHC (g/dl) 36 30–34 quiet and depressed. On 9 Leukocytes (x 10 /l) 18.2 5.0–15.0 physical examination, body Lymphocytes (x 109l) 5.8 1.4–6.1 temperature was 39.7ºC Courtesy of Fundaciò Hospital Clínic and the cat’s mucous Veterinari, Universitat Autònoma de Monocytes (x 109/l) 1.8 0.1–0.6 Barcelona, Spain Band neutrophils (x 109/l) 0 0–300 membranes were pale and dry. Heart rate was 180 beats per minute and pulse strength Segmented neutrophils (x 109/l) 12.0 2.5–11.3 was normal; no murmurs or gallop rhythms were detected. Platelets (x 109/l)* 115 200–600 Clinical dehydration was estimated to be 7%. There were no Serum biochemistry (selected data) other remarkable findings upon physical examination. Owing Result RI to the non-specific clinical signs, blood samples were Albumin (g/l) 24.8 23–34 collected for haematology, biochemistry and feline leukaemia Globulins (g/l) 44.0 26–38 virus (FeLV)/feline immunodeficiency virus (FIV) testing. A urine Total proteins (g/l) 96.9 54–78 sample was obtained by cystocentesis for complete urine analysis. Clinical pathology results are shown in the table. Creatinine (µmol/l) 91 44.2–132.6 Mild leukocytosis with mature neutrophilia and Urea (mmol/l) 8.6 3.32–8.3 thrombocytopenia were observed. Serum biochemistry profile ALT (UI/l) 51.4 <50 showed a mild uraemia, increase in ALT and hyperproteinaemia Urine analysis (cystocentesis) (mainly due to an increase in the globulin fraction). FeLV Result antigen and FIV antibody testing were negative (IDEXX Specific gravity >1.050 SNAP Combo Test). Most of the clinical pathological pH 6 changes were suspected to be due to dehydration. However, Nitrite Negative thrombocytopenia and leukocytosis suggested a possible infectious origin. Ancilliary tests, including an abdominal Protein Negative ultrasound examination and thoracic radiography, were Glucose Negative performed. The results were unremarkable. Ketones Negative Given the patient’s predation habits, leptospirosis was Bilirubin Negative considered and PCR (blood and urine) was performed. In Blood No abnormalities identified addition, serum was serologically examined by MAT against Sediment Moderate fat droplets eight Leptospira serovars: Australis, Autumnalis, Canicola, UPC 0.23 Grippotyphosa, Icterohaemorrhagiae, Javanica, Pomona *Only mild platelet aggregates were observed on blood smear and Sejroe. MAT serology for leptospirosis was negative. RBCs = red blood cells; Hb = haemoglobin; HCT = haematocrit; MCV = mean cell volume; MCHC = mean cell haemoglobin Diagnosis Blood PCR for leptospirosis was positive and urine concentration; ALT = alanine aminotransferase; UPC = urine protein:creatinine concentration; RI = reference interval PCR was negative. Continued on page 226 JFMS CLINICAL PRACTICE 225 216_228_Murillo2.qxp_FAB 03/02/2020 12:44 Page 226 R E V I E W / Leptospirosis in cats Enteral feeding tubes are highly recommend- study suggest further work is needed before a ed in cats with anorexia, until they can feed vaccine against Leptospira­species for cats can themselves in a self-sufficient manner, min- Doxycycline be considered. imising the risk of secondary complications.38 Given the current lack of a vaccine, the best is advised to way to avoid infection in cats is via prevention Antimicrobial therapy of exposure. Cats that are kept indoors have a The antimicrobial therapy suggested in cats is eliminate the lower risk of being infected.37 Prevention of based on the treatment recommended for carrier state. predation opportunities and avoidance of dogs. Intravenous ampicillin may be the contact with stagnant water, urine from infect- antibiotic of choice while the patient is sta- It should be ed animals and dogs at risk of clinical lep- bilised. Once the animal is stable, 6 weeks of tospirosis is recommended.6,30,31,37 For cats doxycycline oral suspension has been sug- administered that share an environment with a positively gested in order to eliminate the carrier state.37 as a diagnosed animal, doxycycline can be given Monohydrate salt of doxycycline, which is less at 5 mg/kg PO q12h or at 10 mg/kg PO q24h irritating to the cat’s oesophagus than hyclate monohydrate for 2 weeks.19,60 or hydrochloride doxycycline salt, is market- salt to avoid ed as tablets or suspension. Doxycycline monohydrate tablets should be administered oesophagitis. immediately before a meal or with a treat in KEY POINTS order to avoid secondary oesophagitis.69,70 ✜ Cats may act as chronic reservoir hosts of Leptospira bacteria and Prevention are a possible risk factor in the transmission and maintenance There is no commercial vaccine available for of leptospirosis, the most widespread cats. However, one study has shown that cats zoonosis worldwide. can produce antibodies (of lower titre magni- tude than vaccinated dogs) when experimen- ✜ Research on leptospirosis tally inoculated with a commercial dog should highlight the vaccine (containing four different serovars).59 importance that cats The follow-up time for the animals was 42 have in the disease days, at which point only one animal main- maintenance cycle. tained antibody levels. The authors of that Continued from page 225 Treatment and outcome The cat was maintained cleaning the litter box during this period, to use routine on fluid therapy and antimicrobial therapy with ampicillin household disinfectants to clean the litter box and to wash (20 mg/kg IV q12h) for 4 days. On day 4 of hospitalisation, their hands after handling their cat. ALT, creatinine and urea were re-checked; values were within Six weeks later, the cat had recovered completely and reference intervals. On discharge, after receiving PCR blood no abnormalities were observed upon physical examination. results, doxycycline at 5 mg/kg PO q12h for 6 weeks was A further urine PCR was recommended in order to rule out prescribed. Instructions were given to keep the animal a chronic carrier state, as well as a further MAT to assess confined during the next 6 weeks and isolated from other seroconversion, but for economic reasons this was not cats and dogs. The owners were advised to wear gloves while approved by the owners. What this case demonstrates: ✜ While leptospirosis is an uncommon infectious disease in cats, practitioners should consider leptospirosis as a differential diagnosis in cats that hunt small rodents. ✜ At the time of admission, clinical pathological data in sick cats are not always characteristic of the disease, as in this case. ✜ For acute infections, PCR on blood and urine is the first-choice test to perform; MAT antibody titres are likely to be negative or low at that point, and seroconversion is not expected until 15 days post-infection. ✜ Leptospirosis is a zoonosis and special handling methods are needed in these cases: (1) avoiding contact with the cat’s urine and wearing gloves when cleaning the litter box; (2) using disinfectants to clean the cat’s litter box as well as any other areas where the cat urinates; (3) preventing the cat from going outside to urinate in the environment; and (4) always washing hands after handling the cat. ✜ Owing to the zoonotic potential of leptospires, prophylactic treatment of other pets in the same household that may have been exposed to leptospires in the environment is recommended. ✜ When a diagnosis of leptospirosis is made, veterinarians should inform pet owners of the zoonotic risk of Leptospira bacteria, and recommend medical attention if any family member develops signs of illness consistent with leptospirosis. 226 JFMS CLINICAL PRACTICE 216_228_Murillo2.qxp_FAB 03/02/2020 12:44 Page 227 R E V I E W / Leptospirosis in cats Conflict of interest detection of feline Leptospira in southern Taiwan. 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