Thank you very much, Bruce, for the introduction and welcome everyone to this webinar on canine leishmaniosis. This webinar is aimed to provide an overview of the key points about this disease that general practitioners in the UK should know. In the webinar, I will start by discussing what leche maniosis is and how it's transmitted.

We'll then move on to discuss the different clinical presentations of leche maniosis that you may encounter in practise and how the disease can be diagnosed. We'll discuss the different drugs that are used to treat the disease and what the optimal approach to managing the disease in the long term should be. And finally, we'll cover the preventative options that should be recommended to any owners who are considering travelling to parts of continental Europe, where the disease is very common.

So, leishmaniosis is a disease caused by protozoan parasites belonging to the genus Leishmania. Over 20 species of pathogenic leishmania have been identified, but by far the most common species that causes disease in dogs is leishmania and phantom. Leishmania and phantom is primarily transmitted by sandflies, which inoculate the parasites into the tissues of dogs during feeding.

Leishmania exists in two different forms, one called the Amato goat and the other called the promastogoat. The promasto goats are the elongated form of the parasite with flagella that live in the gut of the sandfly vectors, while the amasco form is an intracellular ovoid form that exists within the canine host and actually causes the disease. The term leshmaniosis is used to describe the disease occurring in animals, while the term leishmaniasis, where the letter O is substituted for an A, is used to describe disease occurring in humans.

However, sometimes this terminology is used interchangeably, so you may hear some people say either version of this word when describing the disease in dogs. The basic life cycle of leech mania is outlined in this slide. So when this female sandfly feeds, the elongated promastogote forms of leash mania are inoculated into the tissues where they are phagocytosed by macrophages within the dermis.

They then transform into the intracellular amastogote form. The amasto goats replicate within the dog's macrophages until eventually the infected macrophages rupture. Released amastogoats then infect other macrophages that have been attracted to the site of infection.

And if the infected host fails to mount a strong immune response, a mastogoats then spread via the lymphatics and the blood to infect the entire reticular endothelial system of the dog, including the spleen, the bone marrow, and the lymph nodes. Amaster goats can then be ingested by the female sandfly during feeding, and they convert back to this pro-masto goat form over a period of about one week. And this sandfly can then transmit the parasites to other dogs, perpetuating the life cycle of leash mania.

By far the most common means of transmission of leishmania is via the bite of an infected female sandfly. In Europe, only sandflies belonging to the genus Phlebotomus are of importance as the natural vectors of leishmania. Sandflies belonging to this genus are believed to be absent from the UK.

Their endemic range is illustrated in the map on this slide that was published by the European centre for Disease Control, with endemic areas highlighted in red. So we can see from this map that while the flies are not present in the UK, the endemic range encompasses much of southern Europe and extends to parts of central and northern France, so not far from parts of the UK. And statistical models have been developed to predict future climactically suitable areas for sandfly species in Europe under various scenarios of climate change, and most of these scenarios do predict expansion of the endemic range both northwards and eastwards in the next few decades.

So it may be that these sandflies do become endemic in the near future. Female sandflies require the blood from dogs to produce their eggs, and they seek out their hosts shortly after sunset, but they can also feed during the day. And as well as dogs, they feed on a wide variety of other vertebrate hosts, including humans, cats, and livestock.

Although sandfly bites account for the vast majority of canine infections with leishmania, multiple other means of transmission have been identified or suggested. Vertical transmission is one of these routes. Infected bitches have been demonstrated to be capable of transferring the parasite transplacently to infect their offspring.

Rare cases of sexual transmission have also been reported, and blood transfusion represents another possible route of infection if dogs with a history of travel from an endemic area at any time in the past are not screened for leishmaniosis. As we'll discuss in subsequent slides, many dogs with leishmaniosis have subclinical disease and therefore there is a high risk. Of transferring the parasite to the recipient of donated blood from an infected dog.

This is mostly of importance in countries where Leishmania is endemic, but a dog from the UK that has travelled to continental Europe could potentially represent a source of infection to other dogs if used as a blood donor. And therefore, ideally, only non-travel dogs should be used as blood donors in the UK. Direct dog to dog transmission of leishmaniosis has been reported on multiple occasions in North America in populations of foxhounds, where the parasites are believed to have been transmitted via bites and subsequent blood to blood contact in the absence of any sandfly vector.

And isolated cases of direct dog to dog transmission via bites have also been reported in several other countries, including the UK. Finally, much research has gone into trying to identify if transmission can occur via another vector. It's been suggested by some authors that other parasites like fleas or ticks could transmit leishmania, but so far no studies have shown that these these species are capable of transmitting the infection in real life situations.

So really the only natural vector species we know of is the sandfly, which we currently do not have in the UK. In Europe, canine leishmaniasis is endemic in the countries surrounding the Mediterranean basin, including Spain, Italy, Greece, Portugal, and southern France. Leishmaniosis is also found in many other parts of the world, including parts of Asia, Africa, and South America.

You'll notice in this slide that the distribution of leishmania appears to very closely follow the distribution of the sandfly vector species from the map in a previous slide. In highly endemic areas like parts of Spain, the prevalence of infection with leishmania is alarmingly high, so it can approach 80% of all dogs in some areas. So it's a major canine well-being issue as well as a major public health issue in these areas.

And in fact, over 3 million dogs are thought to be infected with leish meiosis in the southwest of Europe alone. The endemic range of leishmaniosis appears to be spreading northwards in Europe in recent years. This may be at least partially explained by a northwards expansion of the sandfly vectors as the climate changes.

But the rate of spread does appear to be relatively slow because sandflies are quite weak flyers and they rarely will travel more than 2 or 3 kilometres from their breeding sites. So this is something that seems to be creeping upwards, creeping northwards, but it's not creeping towards us at an alarming rate. But give it a few decades and we may become more alarmed.

Cases of leishmaniosis are also being increasingly reported in non-endemic parts of Europe, including the UK. The reasons for this are probably twofold increased movement of dogs between the UK and continental Europe, accompanying their owners on holiday, and also increased importation of adopted dogs to the UK from endemic parts of Europe. Because leishmaniosis can have a very long incubation period before dogs show any clinical signs, many of these dogs are imported to the UK when they seem to be clinically normal, and they're only identified to have the disease months if not years later.

Multiple risk factors have been identified and that predispose dogs to develop le meiosis. One of these is age, so dogs who are over 2 years of age are known to be at an increased risk. This probably reflects the time taken to be exposed to the parasites, as well as the incubation period of the disease.

And interestingly, there seems to be a bimodal age distribution with prevalence of cases peaking at around 3 years of age, and then again when dogs are greater than 8 years of age. The second peak at over 8 years of age may reflect the emergence of concurrent disease or weakening of the immune system links to ageing, which may allow a previously dormant infection to turn into clinical disease. Some studies have suggested that certain breeds are at increased risk.

These breeds include German shepherds, boxers, Rottweilers and Dobermans. And interestingly, one breed, the a bean hound, appears to be at a lower risk of developing disease compared to other breeds. We know that dogs with concurrent disease are more likely to develop clinical disease when exposed to leishmania.

And again, this is probably because they are unable to mount a strong an immune response as healthy dogs. Dogs with a prolonged exposure to the outdoors are more likely to develop leash meiosis, probably due to increased exposure to sandflies in the environment, and as you would expect, dogs with a lack of ectoparasiticide prophylaxis are more likely to develop leash maniosis because they're more likely to be bitten by sandflies. Finally, dogs living in areas of poor sanitation, for example, stray dogs or street dogs, are more likely to develop disease.

This is because they're likely to have prolonged exposure to sand lies at the peak feeding times of dusk, and they're unlikely to receive any ectoparasite prophylaxis. Leishmaniosis is always regarded as a chronic disease. The incubation period, that is the time between infection and the development of clinical signs, ranges from 3 months to 7 years, so it can be a very long time.

After exposure, some dogs can completely eliminate the parasite from their body and will never develop any clinical disease. Whereas at the other end of the spectrum, some dogs will develop life-threatening disease. Many dogs will not initially develop disease, but can remain persistently subclinically infected with the possibility of the infection reactivating later in life, especially if the dog becomes immunosuppressed at any point.

In dogs who don't mount a sufficiently robust immune response to the parasite, most of the pathology that occurs is immune-mediated. So we see that T lymphocyte regions in the dog's lymphoid organs become depleted, while there's proliferation of the B lymphocyte regions which produce antibodies. And this leads to an unregulated activation and activity of B cells, causing excess formation of circulating immune complexes in the body.

And these immune complexes can stimulate a complement cascade, cause vasculitis, and cause pathology in multiple organs. The clinical manifestations of le meiosis are quite vast, and they may range from a very mild dermatitis to severe disseminated disease, and lesions can be present throughout the body, leading to changes like polyarthritis, ocular lesions, dermal and mucocutaneous lesions, glomerulonephritis, and occasionally central nervous system involvement. The development of autoantibodies and immune complexes.

Can lead to secondary problems like immune-mediated thrombocytopenia and immune-mediated polyarthritis. And if left untreated, renal failure can occur, and this is in fact the main cause of mortality in patients with leishmaniosis. Because many dogs who develop leishmaniosis come from areas with a high prevalence of other vector-borne diseases, it's quite common for dogs to be co-infected with other pathogens like Erlichia, Babezia, hepatozoan or demodectic or sarcoptic mange.

And so because dogs can be infected with multiple vector-borne diseases, they can have a really variable spectrum of pathology reflecting components of the different infections. And this can make the diagnosis and management of such cases really quite challenging. Some of the more common clinical signs of dogs with leishmaniosis include lethargy, a decrease in appetite, a persistent fever, a chronic weight loss, muscle atrophy, and generalised lymphadenomegaly.

Sometimes splenomegaly may be appreciated on abdominal palpation or on oral examination, you may note pale mucous membranes, and signs like petiation or the presence of joint diffusion. Might be seen in animals with immune-mediated thrombocytopenia or immune-mediated polyarthritis respectively. Dermatological signs are very commonly seen, but to varying degrees.

These signs usually include things like alopecia and scaling, most notably around the pinnae of the ears, around the muzzle, and around the eyes. And many dogs will also exhibit abnormally long or brittle claws, as well as being, among the most common signs of leishmaniosis, skin lesions are also the first signs to develop in most cases. And while signs of leash meiosis can be really variable because it is a multi-systemic disease, if I was to describe the appearance of a classic dog with a leash maniosis, it would be an underweight dog with scaling and alopecia of the periorbital area and on the pinnae with or without a mild generalised lymphoomegaly.

Signs relating to renal dysfunction might be present in dogs who are more severely affected with the disease. So the the chronic exposure to circulating immune complexes causes progressive damage to the glomerulus in the nephron, and this may ultimately lead to a nephrotic syndrome and associated profound proteinuria. And leishmania can also damage the renal tubules and can lead to chronic kidney disease.

So the clinical signs you may see in these patients are broadly similar, similar to those you might expect to see in dogs with iris stage 3 or 4 chronic kidney disease. So for example, polyuria and polydipsia, progressive weight loss, lethargy, or a decrease in appetite. Muucosal pallergy to anaemia is also a frequent finding in leishmania patients.

This may be a result of several different pathological processes in the body, including bone marrow hypoplasia, anaemia of inflammatory disease, or secondary to bleeding from immune-mediated thrombocytopenia. And finally, it's important to note that because le meiosis is a multisystemic disease, it's basically possible for any organ in the body to be affected by the immune dysregulation that occurs. And this can result in an almost endless spectrum of possible pathologies and clinical signs.

So some patients may present with atypical signs. Relating to problems like prostatitis, pancreatitis, or inflammation in various other organs. So, although most cases, you're going to look for signs like these skin lesions on, on the face and on the pinnae and look for non-specific signs like weight loss, in some cases, the signs are much more unexpected, and it really is a disease that can surprise you.

So because it's clear that the range of clinical signs that leishmania can cause is vast and there aren't really any signs that are pathonemonic for the disease, we tend to rely on performing laboratory diagnostics more so than in many other diseases in order to obtain a diagnosis. And here I'd like to discuss what to expect on routine laboratory tests like haematology, biochemistry, and urine analysis, as well as some of the changes that might be observed on diagnostic imaging. And then I'll move on to discuss the tests that can be used to confirm the diagnosis of leishmaniosis.

Although haematology and biochemistry won't give you a definitive diagnosis of le meiosis, it is quite common to see multiple changes on these tests that may help to really increase your suspicion that a dog has leishmania. So on biochemistry, the most consistently present clinical sign is hyperglobulinemia. This occurs in about 75% of cases.

The serum globulin concentration can raise from just very mildly increased to severely increased. And it usually reflects a polyclonal gammopathy, which is where the hyperglobulin anaemia is made up of increases in multiple different immunoglobulin types. In rare cases, monoclonal gammopathy has been reported, and you can use serum protein electrophoresis in cases with profound hyperglobu anaemia, to help you determine whether the high globulin count is more likely to be related to an infection, like le meiosis, where you would expect in most cases to see a polyclonal gammopathy or neoplasia where you would typically expect a more monoclonal gammopathy.

Other changes that may or may not be present on biochemistry include hypoalbuminemia and mild to moderately increased liver enzyme activities. So, albumin is a negative acute phase protein. It decreases in states of systemic inflammation, which is the most likely reason for hypoalbuminemia in dogs with leishmaniosis.

However, other potential causes include loss from bleeding in thrombocytopenic patients, or loss from the kidneys in dogs who are developing a protein using nephropathy. About 20 to 30% of dogs with leishmaniosis are azotemic at the time of diagnosis, and this usually reflects a renal azotemia, indicating renal dysfunction acquired from the disease. On haematology, the most common abnormality to find is a mild to moderate normocytic normochromic non-regenerative anaemia.

This usually reflects either anaemia of inflammatory disease or decreased bone marrow production of red blood cell precursors due to infiltration of the bone marrow with a mastogoole mania. And in about 50% of cases we may also see a mild thrombocytopenia. Less commonly we see a pancytopenia where all three cell lines, the red blood cells, white blood cells, and platelets are decreased.

And interestingly, most dogs with leishmaniosis are lymphoenic on haematology, but a minority of cases have, moderate to marked lymphocytosis, and sometimes this can actually mimic a stage 5 lymphoma or lymphoblastic leukaemia, leading some patients to be misdiagnosed with neoplasia. And the reason some patients with leishmaniosis develop a profound lymphocytosis is really a reflection of the severe immune dysfunction that the disease causes. On urinalysis, the most common abnormality to see is proteinuria, and this usually reflects glomerular injury caused by immune complex disease.

Proteinuria can be quite profound in some patients with le meiosis. So if you do detect proteinuria on your urine dipstick examination, quantifying the proteinuria with a urine protein to creatinine ratio is always advised. Sometimes damage to the renal tubules can also occur, so you may note isoenuria, as you'd expect in a patient with chronic kidney disease, or you may see some casts on urine sediment examination, also indicating tubular damage in the kidneys.

It's quite common that dogs with le meiosis end up having an abdominal ultrasound performed as part of their workup. This may be because splenomegaly was palpated on physical examination, and you're investigating that. It may be because the patient is being worked up for non-specific clinical signs like lethargy or because there is a high index of suspicion for neoplasia if the patient has signs like generalised lymphadenomegaly and weight loss.

The findings on ultrasound can be completely normal in some cases, but often we see some non-specific changes likes splenomegaly, enlargement of intraabdominal lymph nodes, but really ultrasound or imaging elsewhere is unlikely to give you much information in these cases. While general blood tests and imaging in conjunction with the travel history may make us very suspicious a dog has leishmaniosis, none of these will actually provide us with a confirmed diagnosis. So now I'll move on to discuss those confirmatory tests that we can perform.

Visualising a mastic goats off leash mania within macrophages on cytology is one test that can be diagnostic. The organisms are most commonly seen on cytology of skin lesions or on fine needle aspirates of enlarged lymph nodes or the spleen. So you may end up taking fine needle as aspirates from a dog with lymphadenomegaly, expecting to get a diagnosis of lymphoma.

And then when the report comes back from the pathologist, you get a surprise and find that they actually have seen all of these Amatocodes within the lymph node. The emasticos on cytology look like multiple small purple, irregularly shaped bodies within the cytoplasm of macrophages. So they're quite characteristic, but sometimes they're not present in very large numbers, and I always recommend sending slides off to the clinical pathologist for them to have a look at, because it can be something that's quite easy to miss.

Similarly, we can use histopathology of biopsy samples to detect the M mastogotes within macrophages. Other common findings and biopsy samples we might see would include a mixed granulomattis and lymphoplasmaidic inflammation. And although usually Mastogoats will be visible, occasionally only the inflammatory changes are found and no Mastogoats.

So we sometimes need to perform advanced diagnostics like PCR on the biopsy sample to actually confirm the diagnosis of li mania. Some common areas from which biopsies are collected for histopathology would include the bone marrow, which is collected from patients being worked up for pancytopenia or from the skin in patients with severe skin lesions. Serological tests, screening for the presence of anti-leishmania specific antibodies are available from many commercial labs in the UK.

Quantitative serological tests, or that is tests that will give us antibody tighter, are preferable to qualitative tests or tests that will only give us a positive or negative result. And this is because some patients may have a low positive antibody tier if they've been previously exposed to. Mania but have not developed clinical disease.

Whereas animals with clinical disease would be expected on the other hand, to have a very high positive antibody titer. And so the quantitative antibody tests can be very helpful to help us determine whether positive antibody titer is significant or not. And finally, as I briefly mentioned on the previous slide, we will occasionally consider performing PCR to screen for the presence of leishmania DNA on cytology or histopathology samples.

And this is usually where leishmaniosis is very strongly suspected, but where a mastogoats just can't be seen on the samples. Although PC. Is very specific.

It has quite a low sensitivity for detecting leishmania and therefore it's not recommended as a first line test to perform PCR on a blood sample, for example. As a first line test, if you are suspicious for leish meiosis, you should perform quantitative serology, plus or minus cytology or histopathology. Of any abnormalities found during the initial investigations.

So just say you're presented with a dog with skin lesions and you suspect le meiosis due to travel history, I would perform quantitative serology in that patient and I would also perform cytology or histopathology of some of the skin lesions and hopefully those will give you your diagnosis. PCR is really only helpful as an add-on test where the other tests don't give us the diagnosis we're looking for. Now that we've discussed the clinical presentation and the diagnostic workup for leash maniosis, I wanted to briefly mention the leash vet staging system.

So many of you have probably already heard of this resource, especially if you have previously managed a dog with lea maniosis. Levet is an international scientific organisation consisting of vets at multiple academic institutions who have developed some very thorough and easy to follow guidelines on diagnosing and treating leche meiosis. So if you ever have a case in practise, I definitely recommend checking out the leash vet website.

Levet have developed a staging system for canine leashmaniosis, which is summarised in this table. The staging system is useful to determine the prognosis of an individual dog with leishmaniosis. So patients are staged from stage 1, the mildest stage up to stage 4, the most advanced stage, and factors such as the size or degree of the antibody tighter, the severity of the patient's clinical signs, and the presence or absence of azotemia are taken into account when staging a patient.

So you'll notice in the table that dogs with stage 3 and 4 le meiosis have significant renal dysfunction, and that these patients also have a guarded to poor prognosis, which is directly linked to the renal dysfunction. This is in contrast to dogs with stage 1 or 2 disease who are non-azotemic and are generally considered to have a very good prognosis as long as they are diagnosed promptly and treated appropriately. Moving on to treatment, the first point I'd like to make is that unfortunately, regardless of the treatment used, obtaining a complete cure of le meiosis is rare, and lifelong therapy is usually needed to prevent a relapse of clinical signs.

The following are the most commonly used medications to treat leche maniosis. We have meglamine antimonate, allopurinol, and maltaficine. And I'll discuss each of these drugs in turn in the next few slides and then move on to discuss a protocol using these drugs that is typically recommended to manage cases of leishmaniosis.

So starting with melamine antimonase, or just melamine for short, this is a medication that acts by inhibiting protozoal enzymes required for glycolytic and fatty acid oxidation, and ultimately this causes death off the parasites. It's administered as a daily subcutaneous injection of 100 milligramme per kilogramme once a day for 4 to 8 weeks. And possible adverse effects of this medication include the development of cellulitis at the site of injection, because so many injections are required, or the development of nephrotoxicity.

And this is a problem because this means that this particular drug may not be suitable for those dogs with stage 3 or 4 leishmaniosis who already have quite advanced renal dysfunction. It is a very effective drug for treating leishmaniosis, so it's very helpful in dogs with stage 1 or 2 disease, and it gives us the highest chance of obtaining a parasitological cure out of any of the available medications. Although dogs who develop who achieve a cure are still very much in the minority even with this, this drug.

Despite its efficacy, unfortunately, this drug, melamine is not currently available in the UK, although it is widely used in much of continental Europe where the disease is endemic. An alternative medication to melamine is Maltafazine, which acts by activating proteases in the Leishmania organisms leading to their death. Maltafazine is typically administered at a dose of 2 milligrammes per kilogramme orally once a day for 1 month.

And it's a reasonable alternative to melamine when that medication is not available, but the chance of obtaining a parasitological cure is less likely. One advantage of Maltafazine is that because it's an oral medication, it's more owner friendly than meglomine and therefore owner compliance may be better. And an additional benefit is that adverse effects reported from Maltefacine are quite rare.

It's generally very well tolerated, but occasionally dogs may experience vomiting or diarrhoea. This drug is much easier to access than meglamine, but again, unfortunately, it's not available in the UK. Unlike meglamine, however, it can be imported with a special licence for individual cases.

And because this process can be quite challenging, what I would usually recommend is that if you diagnose a patient with le meiosis and you're trying to source maltephicine and having difficulty, if you were to phone your local. Centre, they can often help you or point you in the right direction of how to import this medication, because they, lots of referral centres, especially in the south of England, are starting to see quite a large number of cases of leishmaniosis and have therefore developed quite a lot of experience trying to import this drug. Unfortunately, the need for importation makes the medication very expensive in the UK, whereas it's relatively inexpensive in parts of Europe.

And an example would be, that, you know, a medium sized dog for a one month course could, it could end up being somewhere between 400 and 800 pounds for that one month course. So it's not a cheap medication unfortunately, but it is an effective medication. The final drug to mention is allopurinol, and most of you are probably familiar with this drug for its use in managing urate urolithiasis in breeds like Dalmatians and English bulldogs.

This medication is an oral purine analogue, and it acts by interrupting the synthesis of proteins by Leishmania organisms, and it's typically given at a dose of 10 milligrammes per kilogramme orally twice a day. It's important to look a little bit more specifically at how allopurinol works to understand one of the possible adverse effects of the medication. So specifically, allopurinol acts by inhibiting the enzyme xanthine oxidase in the urea cycle, and this leads to a decrease in the production of uric acid, but an increase in the levels of xanthine within the body.

And these increased levels of xanthine in the body can predispose dogs to form xanthine neuroliths, which can cause some of the typical signs you expect to see with urolithiasis such as stranguria or in more severe cases, urinary tract obstruction. So, because most dogs with le meiosis will need very long term therapy with allopurinol, I typically keep all my patients on long-term allopurinol on a low protein diet like Purina HA and this is to minimise the chance of them developing xanthine urullithiasis as a complication of the allopurinol therapy. Apart from this side effect, allopurinol is usually well tolerated, and it has quite minimal toxicity and it's relatively inexpensive, which is good news compared to the other available drugs.

So having discussed each of these medications individually, I guess the question is what combination of these drugs should you be using if you are presented with a case of leish meiosis in the UK? In general situations, the treatment of choice is using a combination of maltephicine at a dose and frequency of 2 milligrammes per kilogramme orally once a day, and allopurinol given at 10 mg per kilogramme orally twice a day. Melamine would be an ideal choice in substitution for miltefaine in most cases.

However, due to importation rules and regulations, this isn't an option in the UK at present. So we tend to use maltefaine and allopurinol as our routine combination. Miltefazine therapy should be continued for at least 4 weeks and after that, allopurinol is typically continued as a monotherapy.

Allopurinol therapy shouldn't be continued until all the patient's clinical signs have resolved. All of the abnormalities on complete blood count, biochemistry, and urinalysis have resolved, and until your quantitative leishmania serology becomes negative. And so in reality, it's very rare for leishmania serology and all the biochem biochemical abnormalities to completely resolve.

And therefore, in most dogs, it's not possible to discontinue allopurinol therapy. So the majority of dogs do require lifelong therapy, but it is very well tolerated, and the only thing I would really advise in those dogs is to keep them on a diet like Purina HA to decrease the chance of them developing urolithiasis. In addition to the specific therapies for le meiosis, many patients will also require treatment of the complications of the disease or supportive treatment of their clinical signs.

So patients who have developed chronic kidney disease as a result of their leishmaniosis should be screened for complications of their chronic kidney disease like hypertension or proteinuria and treated as a standard chronic kidney disease patient. So depending on the stage of. The chronic kidney disease and how aotemic they are, it may be appropriate to initiate a renal diet.

You may want to start therapy with ACE inhibitors or angiotensin receptor antagonists if they're proteinuric, or you may want to start antihypertensive drugs if they're hypertensive. Appetite stimulants like mirtazapine or placing a feeding tube can be necessary in some patients, in the short term at least who experience profound decrease in appetite. But usually after starting treatment, appetite does improve after a few days to maximum a couple of weeks.

And rarely, patients with severe anaemia as a result of bone marrow suppression or secondary to bleeding from thrombocytopenia may require a blood transfusion, but this is certainly not what is routinely expected. This would be in a minority of patients who are more severely affected. Now that I've discussed how to initiate treatment in these cases, I'd like to discuss briefly what monitoring we typically would advise in these patients.

In general, I advise to check a haematology, biochemistry and a full urinalysis after the first month of therapy. This is to ensure that any haematological and biochemical abnormalities like thrombocytopenia or hyperglobu anaemia are resolving, although it's not expected that all abnormalities will have resolved by this stage. So what you're really looking for is to just make sure you're seeing some signs of improvement, and especially in patients who are azotemic, you want to monitor their azotemia very carefully and make sure that that's not progressing.

The same diagnostics, so haematology, biochemistry, and urinalysis should be repeated every 3 to 4 months in the first year after diagnosis, and thereafter, they should be repeated every 6 to 12 months lifelong. It's also advisable that quantitative serology is checked every 6 to 12 months in the long term. This monitoring is instituted so that we can determine whether or not it might be possible to consider stopping allopurinol therapy at any point in the future.

If you recall from a couple of slides back, I said that it's advisable to continue treatment with allopurinol until all abnormalities on haematology, biochemistry, and urinalysis have resolved, and until quantitative leishmania serology becomes negative. An additional reason for performing this long-term monitoring is that it is possible for clinical disease to recur, even in patients who are on long-term allopurinol therapy, which would necessitate starting another course of maltefazine. In such cases, it's always better to try and identify signs of disease relapse before the patient becomes unwell.

So things you may expect to see are a sudden spike in the quantitative antibody tighter or an increase in your globulins on biochemistry. Leishmaniosis in the vast majority of dogs should be considered a manageable disease, and most dogs will maintain an excellent quality of life while they're on the appropriate treatment. So as an example, the dog in this slide is one I last saw about 6 months ago for a recheck of his le meiosis, which has been successfully treated for the past 5 years.

So his owners give him a twice daily dose of allopurinol. He's brought into the vets for a blood test every 6 to 12 months, but otherwise, in every way, he's a completely normal dog. We typically expect to see a clinical improvement in patients within one month of initiating treatment.

An exception to this rule is patients who have already developed azotemic renal disease, where irreversible kidney damage may have already occurred. And these dogs unfortunately have a guarded prognosis, similar to dogs with advanced chronic kidney disease, regardless of how aggressively we treat their le meiosis. An additional concern is that even in dogs who are on lifelong allopurinol therapy, as I mentioned, there is a chance of relapse of clinical disease within the dog's lifetime, especially if the patient is immunosuppressed for any reason.

So for example, if the patient needs to go on chemotherapy when it's older, or if the patient needs to go on immunosuppressive steroid therapy. And if a patient is going to relapse, this can occur up to several years after the initial presentation of the disease. The prevalence of disease relapse is about 10% of all cases.

And this is another reason why it's a good idea to perform every 6 to 12 months, your routine biochemical tests and your quantitative serology so that you can try and detect any evidence of disease recurrence before the patient becomes unwell again. With leishmaniosis being such a prevalent problem in some parts of Europe, and with it being a disease that is in most cases not curable, preventative measures should be recommended to any owners who are thinking of bringing their dogs over the Channel with them on holiday. So firstly, owners should be made aware of the infections that can be picked.

Up in continental Europe, including Ehrlichiosis, babesiosis, and leishmaniosis, this may make some owners reconsider whether it's a good idea to travel with their pets. But if after being informed of these risks, owners still wish to take their dog overseas, then vaccination is probably the single most effective preventative measure that can be taken. Canelli is an inactive vaccine that's available in the UK against leche meiosis, and it's recommended in all dogs who are over 6 months of age, who will be travelling to endemic areas.

Their primary course involves 3 vaccinations given 3 weeks apart with yearly booster vaccinations needed to maintain immunity. The onset of immunity is 4 weeks after completion of the primary vaccination course. So for this reason, the vaccination course needs to be planned at least 4 months in advance of the anticipated travel date.

Unfortunately, vaccination doesn't provide complete protection against leishmaniosis, and therefore it should always be used in combination with other preventative measures against leishmania. One of these additional preventative measures is the administration of ectopparasiticides, so the use of deltamitrin impregnated dog collars or spot on repellents that contain permethrins like Advantix, for example, can decrease the risk of sandfly bites and subsequent inoculation of leishmania. Keeping dogs indoors at night can also decrease exposure to sandflies, so this should be relayed to all owners, and if you ever have a dog who is positive for release meiosis, it is advisable to neuter that dog and the dog should not be bred from, because if a female dog becomes pregnant, that may cause relative immunosuppression and lead to clinical disease, even if the patient's on therapy.

And also it's known that patients can transmit the infection transplanally. So if these dogs are used for breeding, they could infect their offspring. If you have a very motivated owner, or if you want to be as certain as you can be that a dog won't pick up le meiosis when it travels to continental Europe.

One additional step of protection that can be taken is the administration of an oral medication called Leshguard. This product contains the dopamine D2 receptor agonist medication Domperidone, that acts by enhancing the intracellular killing of leishmania within macrophages. One prospective randomised control study showed that leaguard appeared to effectively prevent transmission of leash meiosis in naive dogs who were exposed to infection, so it appears to be quite effective, and it's typically administered orally once a day for 30 days, starting at the time the dog travels to the endemic area.

So this would be an option, for example, if you had a owner who's travelling to Spain on holiday, they've come just a month before the holiday is due to start and there isn't sufficient time to start a primary course of vaccination. A good alternative in that patient would be to dispense a course of leash guard in addition to the ectoparasiticide treatment. Lee guard is usually well tolerated, and the main side effect that's reported, although it's quite rare, is transient discharge from the mammary glands because Le guard can cause an increase in prolactin concentrations.

So to summarise the preventative options available, all dogs who are travelling to an endemic area should be vaccinated against leishmania prior to travel. A deltamethrin colour or a pyrethrin containing topical ectoparasiticide like Advantix should be administered, and dogs should not have access to outdoors at dusk or overnight when peak sand activity occurs. For an additional level of protection, or if the patient is not vaccinated or doesn't have time to be vaccinated, you could consider also dispensing leash guards.

So I hope that from this webinar, it has come across that leishmaniosis is a major health concern in dogs, but it is worth noting that it's also a significant cause of human disease. In endemic areas, humans can also develop signs of leishmania infection. In humans, it most commonly manifests as skin lesions rather than the systemic form of the disease that is commonly seen in dogs, and we mostly see disease in children and in immunocompromised adults.

Although both humans and dogs can become infected with H meiosis, infection is not regarded as being directly transmissible between dogs and humans. However, dogs do act as a major reservoir of infection for humans, because the more infected dogs there are in an area, the more infected sandflies there will be, who could in turn then spread the disease to humans. So it is technically a zoonotic disease, but it's not directly zoonotic or at least has not been proven to be directly zoonotic.

As many of you will be aware, in 2019, for the first time, cases of leishmaniosis were diagnosed in dogs in the UK that had not travelled for the first time. One of these dogs was the housemaid of a dog in Hertfordshire who had caught le meiosis in Spain, but the dog itself had never left the UK. It was shown that that dog had never received a blood transfusion.

It was castrated, so sexual transmission seemed very unlikely. And its dam was confirmed to be zero negative for leishmaniosis. And therefore, by exclusion of all other causes or all other routes of transmission, it's suspected that this dog was infected by its housemate, most likely through a b a bite and blood to blood contact.

Another unusual case was reported shortly afterwards in Essex, and in another dog who had not travelled. This dog, interestingly, did not live with another dog with leishmaniosis, but still developed the disease. And in this case, the theory was that because the owners of the dog used to live in Spain and travelled back and forth quite regularly and through the year, they had perhaps unintentionally carried some infected sandflies back with them in their luggage, which, which later infected their dog.

Another possibility in that case would be that perhaps there was an undocumented dog bite from an Elemania infected dog, and it became infected in that way. And although these are the only two published cases of leishmaniosis in dogs without a travel history in the UK so far, I am aware of at least 3 additional similar cases that have been presented to different referral centres in the UK over the past few years. So there are more cases out there in non-traveled dogs, but they are still relatively rare.

So, in my opinion, this is a really worrying trend, indicating that the increasing amount of dogs, seroposit for leishmaniosis in the UK do represent an infection risk, albeit a small one, to other dogs. A greater concern is that although the sandfly vector is currently not present in the UK, this could change in the near future as temperatures rise, and having a relatively large population of leishmania positive dogs already present in the UK means that infections could skyrocket should the sandfly ever become established in the UK. When the first cases in non-travel dogs were reported back in 2019, they were picked up by the media and unfortunately there was quite a lot of misreporting and sensationalism of headlines, as you can see from some of the headlines in this slide.

And they reported that the dogs in the cases had died, for example, where, I know that both of these dogs are actually doing very well on treatment. So this misreporting led to somewhat of a backlash from rescue centres based in Southern Europe who organised the importation of rescue dogs to the UK because it was being claimed that leishmaniosis could be transmitted between dogs, which was a claim that they did not agree with. And due to some of the misinformation that circulates online from mainstream media and from some of these rescue centres, it is important as vets to be able to separate the facts from fiction.

So the following are some statements that are often put across, but are not strictly true. The statement that leishmaniosis can't be passed from dog to dog is untrue. This means of transmission has been proven in many different countries, and these cases are published in many scientific journals.

However, this means of transmission, it does appear to be rare. Therefore, a dog who is positive for leishmania represents a very low infection risk to other dogs, but the risk is not zero. Another statement that is not entirely true is that leishmaniosis is a very treatable disease.

In some cases, and in, in most cases, this is true, but we can't forget those dogs that renal disease or dogs who have a delay in their diagnosis, who develop really severe clinical signs and can die from the disease. In addition, in the UK at least, due to importation charges that are applied to the medications we need to use like maltefazine. The cost of medication to treat leishmaniosis can be too much for some owners and ultimately leads to euthanasia.

And finally, it's often reported that dogs with leishmaniosis are not infected with the same strain or species of leash mania that affects humans and therefore they don't pose a zoonotic risk. And while it is true that direct transmission of leash mania from dog to human has not been shown, Leishmania in phantom, which is the species infecting dogs, does infect. Humans and dogs do pose an indirect zoonotic risk to humans in countries where sandflies are present.

So this is not a zoonotic risk in the UK because we don't currently have the sandfly, but in countries like Spain or the south of France, this is a zoonotic disease and potentially could become a zoonotic disease in the UK should the sandfly become established. To finish off, although this webinar is on canine leash maniosis, I wanted to include a slide summarising feline leash maniosis, as it is common for owners to ask if cats can get infected and it's worth knowing. The answer is yes, although cats appear to be quite resistant to leishmaniosis, and they develop clinical disease much less frequently than in dogs.

So it's very unlikely you're going to come across a cat with leishmaniosis in the UK, but it's not out of the question. Disease in cats may be associated with concurrent FIV or FDLV infection, whereby cats are subclinically infected with le meiosis, but then go on to develop clinical disease if they become infected with FIV or FELV and become immunosuppressed. The clinical signs, the diagnostic workup, and the treatment of feline cases of leishmaniosis are broadly similar to canine cases, but cats typically develop lower antibody titers to leach mania than dogs do.

And so, performing quantitative serology in cats, although it's possible to do, is a less sensitive diagnostic tool in this species. And unfortunately, because there are relatively few cases. Lesh meiosis reported, there is quite limited information on the optimal treatment and prognosis of leash meiosis in cats.

However, maltefazine and allopurinol use, like in dogs, has been reported to have good efficacy in cats similar to as in dogs. So that includes the webinar on leash Maniosis. I hope you have found it informative and at this stage, if anyone has any questions, I would be very happy to answer them.

Miles, thank you very much. I think that goes way past informative. It was absolutely fantastic.

Thank you for sharing your time and your knowledge with us tonight. You're welcome. Thank you.

It was interesting to see the, the Lifet, you know, online forum and that because I've, I was gonna say I had the displeasure or pleasure to manage a couple of lash cases, and, the owners always come in and go, well, online they told me I must, and we've got a lash forum and You know, Facebook said I should do this and it becomes very difficult because there is so much information out there and misinformation. Yeah, I, I definitely agree with that, and I would have to say I have come across that as well. So I think, you know, I have had a lot of owners quote the leash vet guidelines, and I think that that's a really good resource and I, you know, I think it's helpful for owners to have a read of that as well to know what to expect.

I have had some owners come in and say that, you know, I've read on the leash vet guidelines that you should not performer. Until 6 months after the initiation of treatment. And so they, they come in and warn you, I say like, don't do serology as if it's going to be a major problem and it's going to be nearly dangerous for the dog to do that.

Whereas in reality, the only reason we don't perform serology for 6 months after diagnosis is because it's probably too early to really read too much into it or to see a decrease in the tier. I do think the Facebook groups certainly are more of a problem, and, and I have come across that as well, whereby there are a couple of quite large Facebook groups with several 1000 owners in them, who, I guess, having heard indirectly from owners about. Sense there there does seem to be quite a lot of opinion about, you know, vets in the UK don't know a lot about leishmaniosis.

They don't really know what they're talking about and you should always consult the Facebook group before speaking to your vet, which I don't personally agree with. But yeah, it is, it is a challenge and it's quite hard to steer owners away from that, unfortunately. Yeah, unfortunately they wind each other up on those forums as well.

We have a question that's come through . It says, thank you for the fantastic presentation. As a student, ages ago, I learned that when you take a dog out of an endemic area, like adopting a or rescuing the dog, that this can cause the disease to clinically manifest itself when they are not having this natural in inverted commas, boosters each year by living in an endemic area.

Is there any truth to this? Hm, I think the, the honest answer to that is that I think it's, it's hard to prove that, and I don't think anyone knows the the definitive answer. So, I guess what what I would say is that it probably doesn't make too much difference if you consider that in in areas like parts of southern Spain, the prevalence of infection is over 80% of all dogs.

You know, I don't think the natural boosters of immunity seem to do very much to prevent it in those cases, or perhaps just the infection burden is too high. But yeah, as to whether or not that's, there's, you know, truth to that, or we have kind of confirmed evidence for it, I, I don't think there are any publications or at least proven evidence that that is a fact, but it's a really interesting point and it might be something interesting to look into. Yeah, fantastic.

Emma asks, if you had a completely healthy seropositive dog, would you treat it living in a non-endemic area or would you wait for clinical signs and to develop ortitis to increase? In that situation, I would probably, I would not treat. So again, as I was saying that we have a lot of sero positive dogs who have subclinical disease or have kind of a dormant disease which may never cause clinical signs.

The medications aren't completely without side effects and are quite expensive. And so if I had a serro positive dog, I would definitely first of all perform the quantitative serology, so you can track that serology over time and see if it's increasing. If it's a sub-clinically affected dog, you would hope that the titer should decrease over time.

So I would typically in that situation, say to recheck serology in about 6 months, see if the titer is increasing. And while you're repeating the serology, I would also perform a haematology and biochemistry, because if you're starting to see haematological or biochemical abnormalities like anaemia or high globulins, that's not consistent with a subclinical infection and in that scenario you should treat. So if the dog is well in itself, haematology, biochemistry.

Are normal and it's just sero positive, I would not treat, but would recheck, bloods in 6 months. If the dog is healthy, is seropos, but has these suggestive biochemical abnormalities like high globulin, anaemia or thrombocytopenia, then in that situation, I probably would treat because you should not see those changes in a subclinically affected dog, and it's likely that the dog is going to become unwell in the near future without treatment. OK.

And, and when you, when you're doing your serology and, and it's, you know, always put a number to it, what changes, because I remember one of my clients was, was very, black and white on this, you know, if it's a 5 unit change, it's important, but you know, 3 units is not, do you have guidelines or is it just a consistent rising tighter or decreasing tighter? Yeah, so there there's no specific cut off. So, yeah, typically, it would just be a rising tighter over a period of greater than 6 months would be regarded as significant, and you would regard that as the disease not being controlled.

Whereas if you're performing repeat serology in a dog who is on treatment for lemania and you already know has the disease, the, the actual degree of decrease doesn't matter that much, but you definitely want to see that the titer is coming down. It doesn't really matter how much it's coming down each time. And ultimately, the only figure that will really matter is if you get a tier of zero eventually, and that's going to mean that you can actually stop treatment in that dog.

Yeah, that's the other controversy of course on all these Facebook groups is the allopurinol. And you know they come up with all these weird things of 3 days on, 2 days off, 5 days on, 7 days off. And you just go really?

I mean. Yes, yes, there are some unique suggestions out there, yeah. It's just crazy.

Miles, that's the end of our questions for tonight. I think that's because you've presented such a fantastically clear webinar. We've got lots of thanks coming through and messages coming to me just saying thank you so much for a very informative webinar.

So thank you once again for your time tonight. You're very welcome. Thank you.

To all of you for attending tonight, thank you very much and to Dawn, my controller in the background, as always, thank you for making things happen seamlessly. From myself, Bruce Stevenson, it's good night.