Leptospira spp. Infection
Edited November, 2018
The Leptospira species infection in cats guideline was first published in Journal of Feline Medicine and Surgery 15 (7), 2013, 576-581. This update has been authorised by Katrin Hartmann.
Leptospirosis is a bacterial disease affecting a variety of domestic and wild animals and humans worldwide that has been reported in over 150 mammalian species. It is considered an emerging infectious disease in humans and in dogs. Subclinically infected wild and domestic animals serve as reservoir hosts and are a potential source of infection for incidental hosts, including humans (Adler and de la Pena Moctezuma, 2010; Sykes et al., 2011; Schuller et al., 2015).
Leptospira spp. infection in cats is common, and cats usually acquire the infection from hunting rodents. The disease leptospirosis in cats is considered rare, but the number of reports on field cats with clinical signs caused by Leptospira spp. infection increases, and the disease has recently been seen more commonly (Murphy, 2015). In addition, the fact that cats can shed Leptospira spp. with their urine and thus, serve as a potential source of infection has gained increasing attention (Weis and Hartmann, 2017). Antibodies against Leptospira spp. are commonly present in the feline population, and Leptospira spp. shedding in cats with outdoor exposure has been demonstrated now in different regions worldwide (Fenimore et al., 2012; Rodriguez et al., 2012; Dorsch et al., 2017; Sprißler et al., 2017; Weis et al., 2017). The role of healthy carrier cats as source of contamination as well as the role of leptospires as a pathogen in cats likely has been underestimated in the past.
Leptospires are mobile, thin, filamentous bacteria of a size of 6.0-25 mm length and 0.1-0.2 mm width, that appear as fine spirals often with hook-shaped ends (Fig. 1) (Bharti et al., 2003; Adler and de la Pena Moctezuma, 2010). They actively move by rotating around their axes, with clockwise rotation resulting in hook-shaped ends and counterclockwise rotation resulting in spiral-shaped ends (Wolgemuth et al., 2006). Leptospires can remain infectious for several months under optimal environmental conditions, such as at temperatures around 25 °C, moisture, and a neutral soil pH (Sykes et al., 2011; Schuller et al., 2015).
The genus Leptospira belongs to the order Spirochaetales. There are over 250 pathogenic serovars of leptospires, based on differences in the carbohydrate component of the bacterial lipopolysaccharide. Serovars are grouped into antigenically related serogroups. Immunity to leptospires is serogroup-specific. Different serovars are adapted to different wild or domestic animal reservoir hosts. Leptospirosis in dogs and humans is caused primarily by pathogenic serovars of the species Leptospira interrogans sensu lato. Several of those serovars also have been reported to cause infections in cats (Sykes et al., 2011; Dorsch et al., 2017; Sprißler et al., 2017; Weis et al., 2017).
In dogs, serovars Icterohaemorrhagiae and Canicola were responsible for most cases of canine leptospirosis before 1960. Since the widespread use of a bivalent serovar-specific vaccine against Canicola and Icterohaemorrhagiae, there has been an apparent shift to other serovars that are now more commonly identified in dogs suffering from leptospirosis. This has subsequently led to an increase in canine cases (Sykes et al., 2011; Schuller et al., 2015). In the last ten years, new vaccines for dogs have reached the market in USA and several European countries, which contain not only Canicola and Icterohaemorrhagiae, but also Grippotyphosa, and in some vaccines additionally Bratislava (or Australis which is in the same serogroup) or Pomona, and this has now again decreased the incidence of leptospirosis in dogs in countries where new vaccines are used (Francey et al., 2018).
Leptospires can cause infections in many animal species, and have been identified in more than 150 mammalian species as well as in bird, fish, amphibian, and reptile species (Everard et al., 1985; Pappas et al., 2008). Subclinically and often chronically infected wild and domestic animals serve as reservoir hosts and shed leptospires mainly through urine, and thus, are a potential source for contamination of the environment. Mainly rodents serve as reservoir hosts, but also companion and production animals, such as dogs, pigs, and cattle (Adler and de la Pena Moctezuma, 2010; Mayer-Scholl et al., 2014; Llewellyn et al., 2016).
Leptospires are transmitted by direct contact or indirectly. Direct transmission between hosts occurs through urine, venereal routes, placental transfer, bites, or ingestion of infected animals or tissues. Spirochaetales have also been demonstrated to survive in insects and other invertebrates, but their role as vectors of Leptospira spp. is unknown. In dogs and humans, indirect transmission is more frequent than direct transmission and occurs through exposure to contaminated environment, e. g., soil, food, or bedding. Thus, water contact is most important in dogs and humans, and habitats with stagnant or slow-moving warm water favour survival of the organism. Leptospires in contaminated water invade the host through skin wounds but also through intact mucous membranes (Sykes et al., 2011; Schuller et al., 2015). In cats, indirect transmission through water contact is less likely (Hartmann et al., 2013; Weis et al., 2017), likely due to their natural aversion to water. Cats are thought to most commonly get infected through direct rodent contact. It has been shown experimentally that feeding on rodents harbouring leptospires can lead to infection in cats (Shophet and Marshall, 1980). Rodents are the natural reservoir for many serovars, and prey-predator transmission between cats and rodents seems to occur commonly (Shophet, 1979). In Germany, in almost 10% of rodents, DNA of pathogenic leptospires was detected (Mayer-Scholl et al., 2014). On Reunion Island, DNA of pathogenic Leptospira spp. was found in kidney samples of more than 50% of rodents (Desvars et al., 2013). In France, 44% of wild rats tested positive by PCR or culture (Ayral et al., 2015). The risk of infection for cats hunting rodents is therefore considered relatively high (Desvars et al., 2013).
As pigs and cattle can shed leptospires subclinically, production animal farms are another source of infection for cats (Everard et al., 1985; Harkness et al., 1970, Truong et al., 2013). In one study in Iran, cats in contact with dairy cattle herds were significantly more commonly infected than cats in urban areas (Talebkhan Garoussi et al., 2015). In a recent study, interspecies transmission of pathogenic Leptospira spp. between livestock and a domestic cat dwelling in a dairy cattle farm in Chile was demonstrated. The cat was physically healthy but had leukocytosis with neutrophilia, monocytosis, and hyperproteinaemia. Urinary shedding was detected by PCR, and the cat had microagglutination test (MAT) titres against serovars Pomona and Autumnalis. The cattle herd in contact with the cat also had evidence of Leptospira spp. infection (Ojeda et al., 2018). Dogs also can be chronic shedders of Leptospira spp. (Harkin et al., 2003a; Rojas et al., 2010; Gay et al., 2014; Llewellyn et al., 2016). Due to the low pH, Leptospira spp. can only survive for a short time in the urine of dogs. Nevertheless, infection of cats by direct contact with urine from dogs or other cats is possible (Hartmann et al., 2013).
Antibodies have been detected in cats worldwide (Larsson et al., 1985; Batza and Weiss, 1987; Dickeson and Love, 1993; Agunloye and Nash, 1996; Luciani, 2004; Mylonakis et al., 2005; Markovich et al., 2012; Rodriguez et al., 2012; Lapointe et al., 2013; Rodriguez et al., 2014; Talebkhan Garoussi et al., 2015; Weis et al., 2017; Rose et al., 2016; Sprißler et al., 2017; Weis et al., 2017). Antibody prevalence varies depending on geographical area and climate, and according to recent studies ranged from 4.8% in the United States (Markovich et al., 2012) to 48.5% in France (Luciani, 2004). Two studies in Germany detected antibodies in 14.6% of cats in the Berlin (Rose et al., 2016) and 17.9% of cats in the Munich area (Weis et al., 2017). Reactivity to many different serovars has been identified in cats based on MAT, including reactivity against serovar Anhoa, Australis, Autumnalis, Ballum, Bratislava, Canicola, Djasiman, Celledoni, Copenhageni, Grippotyphosa, Hardjo, Icterohaemorrhagiae, Pomona, Pyrogenes, and Saxkoebing (Larsson et al., 1984; Batza and Weiss, 1987; Dickeson and Love, 1993; Agunloye and Nash, 1996; Mylonakis et al., 2005; Markovich et al., 2012; Rodriguez et al., 2012; Rose et al., 2016; Sprißler et al., 2017; Weis et al., 2017). Prevalence of serovars differs significantly between geographical regions. Most studies based on antibody detection have used MAT. However, cross-reactions between serovars can occur, and therefore, serovar prevalence studies are difficult to interpret. No correlation was found between antibodies and sex or breed. However, an association with age has been reported, with old cats being more likely to possess antibodies (Larsson et al., 1984; Mylonakis et al., 2005; Rodriguez et al., 2012). Antibodies are more common in outdoor cats, those living in urban areas, and those that are known hunters (Rodriguez et al., 2012).
Recent studies have looked into shedding of Leptospira spp. in the urine of cats using PCR in a few countries. Prevalence ranged from 0.8% in Thailand (Sprißler et al., 2017), 3.3% in Germany (Weis et al., 2017), 3.4% in Canada (Rodriguez et al., 2012) to 11.7% in the United States (Fenimore et al., 2012) and 13.0% in Chile (Dorsch et al., 2017). In a study in Taiwan, prevalence of Leptospira spp. urinary shedding of 67.8% was detected (Chan et al., 2014), but sampling had occurred following a natural disaster that had caused an unusual epidemic of leptospirosis in humans (Su et al., 2011). Recently it was possible to prove that cats not only shed leptospiral DNA, but truly viable leptospires. This was demonstrated in two studies in Chile, in one study, in which viable leptospires were cultured in the urine of outdoor cats (in 1.3% of the tested cats) (Dorsch et al., 2017) and in one report of interspecies transmission between a cat and a dairy cattle farm (Ojeda et al., 2018). It is important to realize that some cats also shed lesptospires without having detectable antibodies (Shophet, 1979; Sprißler et al., 2017), and that some cats might shed over a long period of time. In one of the shedding cats in Germany, a follow-up urine sample eight months after the first sampling was positive again for leptospiral DNA, indicating a chronic carrier state or reinfection (Weiss et al., 2017). Prevalence of urinary shedding is comparable to that of dogs in the same areas (Fenimore et al., 2012; Llewellyn et al., 2016; Weis et al., 2017). However, while dogs in Europe most commonly have Leptospira spp. infection in late summer and autumn/fall (Schuller et al., 2015), in cats no seasonal peak was found (Weis et al., 2017). The reason for this likely is the difference in transmission of leptospires, which in dogs is more dependent on the outside temperature.
All these studies show, that outdoor cats might be a reservoir or incidental hosts for the transmission of leptospires. Likely, urinary shedding and the role of cats as a source of infection have been underestimated in the past.
Wild felids can also be infected with Leptospira spp. In 2/57 healthy captive felids in Brazil, antibodies against Leptospira spp. were detected (Ullmann et al., 2012). In addition, jaguars in various areas in Brazil had antibodies against different Leptospira serovars (Furtado et al., 2015).
The pathogenesis of feline leptospirosis is not well known but is likely similar to that in dogs and humans. Infection occurs via direct contact with a host or its urine, or indirectly via contaminated soil or water (e. g., drinking or bathing). After penetration through mucous membranes, abraded or scratched skin, leptospires multiply rapidly upon entering the blood vascular space as early as one day after infection and can circulate up to seven days in the blood. They invade the kidneys, liver, spleen, central nervous system (CNS), eyes, and genital tract amongst others, and can damage these organs by replicating and causing inflammation (Alder and de la Pena Muctezuma, 2010). Initial replication mainly causes damage to kidneys and liver. The extent of damage is variable and depends on virulence of the organism and host susceptibility. The immune response can clear the leptospires from most organs except from the kidneys, where the agent can persist (Levett, 2001; Schuller et al., 2015). In dogs, shedding can continue for weeks to months (Alder and de la Pena Muctezuma, 2010; Sykes et al., 2011) and this might be the case in cats as well (Weis et al., 2017).
Although Leptospira spp. infection and shedding in cats seems to be as common as in dogs, clinical disease is less frequently observed. However, during a recent outbreak of leptospirosis in dogs in UK, several cats with clinical signs of leptospirosis were identified (Murphy, 2015).
There are few experimental studies in which cats have been infected with pathogenic Leptospira spp. Disease after experimental infection was usually mild, or infection remained subclinical (Agunloye and Nash, 1996; Dickeson and Love, 1993; André-Fontaine, 2006). Some cats showed mild clinical signs, such as polyuria/polydipsia, mild diarrhoea, and a slight increase in body temperature (Semmel, 1954; Fessler and Morter, 1964; Larsson et al., 1985). Laboratory diagnostics revealed a mild leukocytosis (Semmel, 1954). Six of seven experimentally infected cats had an enlarged liver at necropsy, and histopathological degenerative changes of the liver were noted. Five of seven cats showed non-purulent interstitial nephritis (Fessler and Morter, 1964).
A few case reports about cats with leptospirosis in the field have described the disease in outdoor and hunting cats (Bryson and Ellis, 1976; Arbour et al., 2012; Murphy, 2015). The most common clinical manifestation after natural infection seems to be an interstitial nephritis (Hemsley, 1956; Rees, 1964; Fessler and Morter, 1964; Arbour et al., 2012), and affected cats are presented with acute polyuria/polydipsia, anorexia, and lethargy (Arbour et al., 2012). In one case series of three cats with leptospirosis, all cats had renal disease without liver involvement (Arbour et al., 2012). In an older case description, a cat with ascites, enlarged liver, and impaired hepatic function, but without icterus, had antibodies against serovar Hardjo (Agunloye and Nash, 1990). Leptospires also have been isolated from thoracic fluid, aqueous humour, and kidneys of a cat, which at necropsy had widespread haemorrhages and straw-coloured fluid in the thoracic and peritoneal cavities (Bryson and Ellis, 1976).
A relation between polyuria and polydipsia and the presence of antibodies against Leptospira spp. has been suggested (Luciani, 2004; André-Fontaine, 2006). Two recent studies indeed described an association between the presence of antibodies against Leptospira spp. and chronic kidney disease (Luciani, 2004; Rodriguez et al., 2014). While 14/16 cats with polyuria/polydipsia (87.5%) had antibodies against leptospires, only 32/80 healthy cats (40.0%) were antibody-positive (Luciani, 2004). In another study, 17/114 cats with renal disease (14.9%) had antibodies, while only 9/125 healthy cats (7.2%) were antibody-positive, which represented a significant difference (Rodriguez et al., 2014). However, other studies found no association between chronic kidney disease and the presence of antibodies against leptospires. While 4/66 azotaemic cats had antibodies (6.1%), 8/75 cats without azotaemia (10.7%) were antibody-positive (Shropshire et al., 2016). In a German study, there was also no correlation; 5/24 clinically healthy cats (20.8%) and 8/28 chronically ill cats (28.6%) had antibodies (Weis et al., 2017). A correlation between excretion of leptospires and chronic kidney disease in cats was also investigated in a study which found that 2/125 (1.6%) clinically healthy cats and 6/113 (5.3%) cats with chronic kidney disease were urine PCR-positive; however, this difference was not significant (Rodriguez et al., 2014).
Immunity after infection with Leptospira spp. is considered to be only short-lived. In dogs, true duration of immunity after natural infection is unclear, and it is unknown whether or not life-long immunity can develop after natural infection. So far, there are no reports of reinfection of dogs with Leptospira spp. after successful treatment. Immunity to leptospires is serogroup-specific, with little cross-protection between different serogroups (Schuller et al., 2015).
Recovery from infection depends upon production of specific antibodies. Antibodies are usually detectable three to ten days after the presence of first clinical signs (Merien et al., 1995; Levett, 2001; Sykes et al., 2011). In an experimental study, cats developed antibodies detectable in MAT three weeks after infection (Shropshire et al., 2016). As antibodies increase, leptospires are cleared from most tissues, except from the kidneys. Renal colonization occurs in most infected animals, and the organism usually persists in the tubular epithelial cells causing shedding for months to years after clinical recovery (Sykes et al., 2011; Greene et al., 2012; Schuller et al., 2015).
Many cats are infected with leptospires, but do not develop clinical signs (Hartmann et al., 2013). Consequently, the diagnosis “feline leptospirosis” should only be made when associated clinical signs are present (Weis and Hartmann, 2017).
Direct detection of the leptospires
Direct pathogen detection (especially from urine samples) in cats is particularly important to assess a potential zoonotic risk (Weis et al., 2017). Direct identification of the organisms can be achieved by several techniques, including visualization in fresh urine by dark-field microscopy or in tissue sections or on air-dried smears by light microscopy, culturing of the organism, or detection of DNA by PCR. All direct methods, however, are only reliable if a positive result is obtained, and a negative result never excludes the presence of the infectious agent due to the fact that leptospires are only shed intermittently and sometimes in low numbers (Levett, 2001).
Direct identification of viable leptospires by dark field microscopy is not reliable and thus not recommended (Levett, 2001; Hartmann et al., 2013). A more reliable method is antibody staining (by immunofluorescence or immunoperoxidase), which can be used to identify leptospiral agents in body fluids and cytological samples of organs, such as liver or kidneys (Fig. 2), if appropriate samples are available (Adler and de la Pena Moctezuma, 2010).
Leptospires can be cultured from the urine, blood, and cerebrospinal fluid (CSF), but grow very slowly. Cultures usually take weeks to months before becoming positive (Dorsch et al., 2017), and reliable results can only be expected when the animal had not been pretreated with antibiotics. Thus, in most cases culture is not a useful option in practice.
PCR methods are available to detect leptospiral DNA in body fluids, including urine, blood, CSF, and aqueous humour (Bal et al., 1994; Merien et al., 1995; Harkin et al., 2003a; Harkin et al., 2003b) and have been shown to be applicable to cats (Fenimore et al., 2012; Rodriguez et al., 2012; Dorsch et al., 2017; Sprißler et al., 2017; Weis et al., 2017). In humans, PCR was shown to be more reliable in early diagnosis than antibody testing or culture (Brown et al., 1995). PCR to identify DNA from organisms in urine, where it reaches high concentrations, has been experimentally shown to be sensitive and specific, and it allows a diagnosis at an early stage of infection. However, PCR is only useful in animals not previously treated with antibiotics and can be negative in infected cats due to intermittent shedding (Levett, 2001).
Antibodies can be detected using the MAT or an enzyme-linked immunosorbent assay (ELISA). MAT is the most common diagnostic method to detect antibodies in dogs and humans. It is also the antibody test of choice in cats and has been validated for cats (Larsson et al., 1984; Batza and Weiss, 1987; Agunloye and Nash, 1990; Dickeson and Love, 1993; Mylonakis et al., 2005; Markovich et al., 2012; Rodriguez et al., 2012; Shropshire et al., 2016; Sprißler et al., 2017; Weis et al., 2017). However, as shown in dogs, the MAT has marked limitations with regards to sensitivity, specificity, and repeatability, especially if single titres are interpreted (Miller et al., 2011; Fraune et al., 2013). MAT is not serovar-specific (Sykes et al., 2011; Schuller et al., 2015), and cross-reactions make identification of the infecting serovar difficult. Infected animals can be antibody-negative in the acute phase of the disease, due to the normal delay in appearance of serum antibodies. In addition, different serogroup antigens are included in the assay, and false-negative results will occur when the infecting serogroup is not included. In dogs, widespread use of vaccines also limits usefulness of the MAT. Non-infected dogs vaccinated with whole cell anti-leptospiral vaccines, especially with the new ones that contain four serovars, can have post-vaccinal titres of 1:6400 or higher to both, vaccinal and non-vaccinal serovars (Barr et al., 2005; Martin et al., 2014; Midence et al., 2012), and vaccinal titres can even persist for twelve months in some dogs (Martin et al., 2014). Reactivity of anti-leptospiral antibodies with multiple serogroups often prevents the determination of the infecting serogroup. Moreover, the serogroup with the highest MAT titre can vary over time, indicating that the MAT does not reliably predict the infecting serogroup in infected animals (Miller et al., 2011). Although there is no vaccine in cats and thus, diagnostic interference with vaccine antibodies can be excluded, in cats variation of results between laboratories and differences in humoral immune responses make correct interpretation of MAT results problematic.
In-house tests to detect immunoglobulin G (IgG) or IgM antibodies in dogs are now available. However, although potentially useful in dogs (Lizer et al., 2017; Lizer et al., 2018), such tests have not been evaluated in cats.
Treatment of dogs consists of supportive therapy and antibiotics, and the same should be done in cats with leptospirosis. Supportive treatment depends on the severity of clinical signs and the presence of renal or hepatic dysfunction and other complicating factors. Treatment of acute kidney injury is the most critical aspect in dogs and the same is likely true for cats. Acute kidney injury with anuria commonly requires renal replacement therapy with haemodialysis that is life saving for many animals with severe anuric leptospirosis. Thus, animals should be referred early to facilities with haemodialysis. Haemodialysis is indicated in animals with inadequate urine output that are developing volume overload, hyperkalaemia, or signs of uraemia that are not responsive to medical management. The extent of renal damage after treatment determines the overall prognosis (Sykes et al., 2011; Schuller et al., 2015).
Antimicrobial therapy usually consists of two stages. The first stage is aimed to immediately inhibit multiplication of the organism and rapidly reduce fatal complications of infection, such as hepatic and renal failure. Penicillin and its derivatives are the antibiotics of choice for terminating Leptospira spp. replication. Initially, ampicillin (20 mg/kg q 8 h IV) or amoxicillin, if available for IV use (20 mg/kg q 12 h IV), should be given parenterally to a vomiting, uraemic, or hepatically compromised animal. These drugs prevent shedding and transmission of the organism within 24 hours of initiation of therapy. They are neither able to clear the infection from the kidneys nor to prevent a carrier state with chronic shedding. In the second stage, other drugs should be administered to address the carrier state. Doxycycline (5 mg/kg q 12 h PO for three weeks) is the drug of choice, and treatment should start as soon as the clinical condition allows its oral application (Sykes et al., 2011; Schuller et al., 2015). Intravenous application of doxycycline is not recommended in cats because it can cause shock and vomiting, and subcutaneous injection can lead to development of abscesses in cats. Doxycycline can also cause liver toxicity. Thus, it should only be started after the animal has stopped vomiting, and liver enzyme activities are in the reference range. In cats, use of doxycycline suspension is preferred over tablets or capsules to lower the risk of oesophagitis and secondary oesophageal strictures, especially with some doxycycline salts (hyclate) (German et al., 2005; Trumble, 2005). In animals without clinical signs or with only mild signs, doxycycline can be used for both, initial and elimination therapy (Sykes et al., 2011; Schuller et al., 2015).
If healthy cats are identified to shed leptospires, treatment with doxycycline (5 mg/kg q 12 h PO for three weeks) should be initiated to control the carrier state (Weis and Hartmann, 2017). This minimizes the risk of infection for other animals and humans. However, in hunting cats, reinfection with leptospires is possible. Testing for Leptospira spp. shedding in healthy cats might be indicated if the owner is immunosuppressed or if an animal or human being in the household is diagnosed with leptospirosis.
Although several vaccines are on the market for dogs, no vaccine is available for cats. To avoid cats getting infected with Leptospira spp., cats should be prevented from feeding on (potentially infected) rodents and be kept away from stagnant water. Cats that are kept indoors only have a very low risk of infection (Weis and Hartmann, 2017).
The number of people suffering from leptospirosis worldwide is currently estimated at over 1 million per year. The number of people that die from the disease is estimated to be around 60,000 per year (Costa et al., 2015).
The role of cats in the transmission of leptospires to humans is unclear. Since cats can shed viable leptospires in their urine, they are considered to have a zoonotic potential, and appropriate precautions should be taken when handling cats potentially infected, such as disinfection of hands after contact with urine or prey, antibiotic treatment of cats shedding leptospires (Weis and Hartmann, 2017). One study investigated the role of introduced feral cats as a reservoir for infecting humans on a tropical Christmas Island, where a recent case of human leptospirosis had been detected. Pathogenic leptospires were found by PCR in kidney samples of 42.4% of investigated cats (Dybing et al., 2017). In order to minimize the risk for people handling Leptospira spp.-shedding cats, e. g., in a veterinary clinic, the same precautions should be taken as if handling a Leptospira spp.-infected dog, such as wearing gloves and goggles and taking specific measures when handling urine-contaminated areas and objects, such as litter boxes.
On the other hand, cats might reduce their owners’ risk of infection by eliminating reservoir hosts (e. g., rodents) and thus, minimizing the continuous environmental spread of leptospires (Childs et al., 1992). Especially in tropical countries, cats also reduce the direct contact of humans with rodents by minimizing rodent density. In a study in Nakhon Ratschasima, Thailand, twice as many people of an uninfected control group (25/129, 19.7%) owned cats compared to people that were infected with leptospires (5/49; 10.2%) (Tangkanakul et al., 2001). Also, in a study in Baltimore, USA, people living with cats were less likely to have antibodies against leptospires than people without cat contact. Keeping cats as pets was determined as a protective factor for leptospiral infection (Childs et al., 1992).
ABCD Europe gratefully acknowledges the support of Boehringer Ingelheim (the founding sponsor of the ABCD) and Virbac.
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