Thick Borne Disease.docx

**[Thick Borne Disease (Lyme Disease) & Pet travel:]** 1. **[Learning Objectives:]** Welcome to Week Two, Lesson Two of Canine infectious Diseases. In this lesson, we\'re going to focus on Lyme disease before exploring some very interesting global tick borne diseases. Simon Tappin MA VetMB Cert...

**[Thick Borne Disease (Lyme Disease) & Pet travel:]** 1. **[Learning Objectives:]** Welcome to Week Two, Lesson Two of Canine infectious Diseases. In this lesson, we\'re going to focus on Lyme disease before exploring some very interesting global tick borne diseases. Simon Tappin MA VetMB CertSAM DipECVIM-CA FRCVS  **By the end of this lesson, you should be able to:** 1. Explain why ticks are good vectors for disease using knowledge about their life cycles; 2. Recall the clinical signs associated with Borrelia (Lyme disease); 3. Outline how to make a diagnosis of Borrelia infection; 4. Consider the treatments options for Borrelia infection and the preventative options available; 5. Reflect on the PETS travel scheme and its impact on imported diseases. 2. **[Tick Borne Diseases:]** Canine tick-borne diseases are uncommon, but their incidence and consequently public awareness is increasing. Many factors are involved, including changes to tick populations and distribution, pets travelling abroad and being exposed to novel tick vectors and their associated diseases, as well as increased vigilance and more available diagnostic techniques. Simon Tappin **Warmer climates** through northern Europe have allowed tick populations to expand their distribution and milder winters have led to increased tick numbers. As a result, the prevalence of endemic diseases, such as Lyme disease, has increased significantly in man over the last decade and the incidence of suspected canine cases has also increased. Diseases not usually seen in the United Kingdom, such as Borrelia and Ehrlichia, have been seen as a result of travel to mainland Europe and recently cases of both diseases have been reported in untraveled animals, prompting concerns that these diseases may become endemic in the British tick population. 3. **[Questing:]** Ticks are very well adapted parasites. They are capable of finding a host by detecting breath and body odours and by sensing body heat, moisture and vibrations. Some species can even recognise shadows. Simon Tappin  Ticks can also identify well-used paths where they wait for a host, resting on the tips of grasses and shrubs. Ticks can't fly or jump, but many species wait in a position known as "questing" which means they hold onto leaves and grass by their third and fourth pair of legs. Once there, they hold the first pair of legs outstretched, waiting to climb onto the host. When a host brushes the spot where a tick is waiting, it quickly climbs aboard. Some ticks will attach quickly and others will wander, looking for places like the ear, or other areas where the skin is thinner and they are less likely to be easily displaced.  Once in position, ticks have a **large number of adaptations** which make feeding as easy as possible. Firstly, they have very **sharp mouth parts** which enable them to feed on blood in the subcutaneous capillary beds and they inject material around them called tick cement which makes it difficult for them to be dislodged. Secondly, they have a number of **salivary components** which help them feed but also evade the immune system. **Anticoagulant** and **vasodilatory compounds** help feeding and anti-inflammatory molecules and immunomodulators help the tick to avoid the host's immune system. The YouTube animation below shows these processes, but also how disease-causing organisms can be transmitted from the tick\'s salivary glands and intestines when the tick feeds or if the tick regurgitates due to it being compressed or irritated during tick removal.  Tick Feeding Process 4. **[Tick Lifecycles:]** Ticks have **long life cycles** requiring them to **feed** on **several different hosts** **at different stages**, making them **extremely efficient vectors** of **disease**. Simon Tappin  Tick-borne diseases are tightly confined to the area of the tick vector, so increasing travel through the PETS scheme leads to increased exposure to unusual tick vectors and disease, with cases of Ehrlichia and Babesia regularly reported. The concern regarding tick-borne disease is not limited to exotic disease. In the United Kingdom, Lyme disease has been documented in increasing frequency in man, with cases of suspected disease in dogs also increasing. In part, this is due to increased awareness, better diagnostic tests and statutory reporting of cases in people, however, there is also evidence that the tick populations and **distributions** are **changing** as a result of **climate change**. The **warmer climate** has led to ticks moving into new areas, for example, *Dermacentor reticulatus* (the European Meadow tick) which is usually found in southern Europe, is now established in Poland, Belgium and Germany, with increasing numbers being found in the United Kingdom. It is also thought that milder winters are reducing tick mortality, leading to increasing tick numbers. A recent study found that 15% of dogs were carrying ticks without their owners being aware of their presence, documenting infestation and the potential opportunity for the transfer of infection. Afbeelding met diagram Automatisch gegenereerde beschrijving 1. Six legged larva feeds on a small mammal, then drops off to the ground and moults 2. Eight legged nymph feeds on a small mammal, then drops to the ground and moults 3. Eight legged aduts feed and mate on a larger mammal, including livestock and pets, then drop off to the ground. Males die soon thereafter and females begin to develop eggs 4. Female tick lays eggs on the ground  5. **[Tick Populations in the UK:]** Read the following open access paper which documents the different tick populations in the UK. These are mainly hard shelled Ixodes species, such as *Ixodes ricinus *(the sheep or castor bean tick) and *Ixodes hexagonus* (the hedgehog tick), but there are small pockets of *Dermacentor reticulatus* (the ornate cow or meadow tick) and* Ixodes canisuga* (the UK dog tick). The findings from the paper allow the calculation of the relative risk of dogs encountering ticks in different areas of the UK, with younger dogs and those of pastoral and gundog breeds most likely to come into contact with ticks. Simon Tappin  **Ticks infesting domestic dogs in the UK: a large-scale surveillance programme ** [**CLICK HERE(OPENS IN A NEW TAB)**](https://parasitesandvectors.biomedcentral.com/articles/10.1186/s13071-016-1673-4) In addition to the changes in the UK population, due to increases in pet travel, imported ticks are being seen with an increasing frequency. The tick *Rhipicephalus sanguineus* (the brown dog tick), is not native to the UK but is an important vector for many diseases in mainland Europe (especially Babesia and Ehrlichia as we will cover in the next lesson). The UK is not warm enough for this tick to reproduce in the wild, but in centrally heated houses they can survive very well and have a prolific capacity to produce offspring, with each female being able to produce up to 7000 eggs. The Animal and Plant Health Agency (APHA) are reporting increasing numbers of these ticks being found on animals entering the UK and there are reports of dwellings needing to be fumigated to remove the ticks from properties.   6. **[Case Example -- Bradley:]** Let's have a look at a case -- this is Bradley, a seven year old male neutered Springer Spaniel. Simon Tappin  1. **[History:]** He has a three week history of not being quite right, with lethargy, listlessness and inappetence. In addition, in the seven days prior to presentation, he had developed a shifting leg lameness. This was described by the owners as him appearing to walk on eggshells and it was very difficult for them to identify which leg he was uncomfortable on. 2. **[Clinical Examination:]** At presentation, Bradley was very quiet and had a moderate pyrexia (39.8˚ C). **Joint effusions** were easily palpable in all the distal joints (carpi and tarsi), with pain elicited on forced flexion of these joints. Effusions in the elbows and stifles were not palpable. No neck pain or other foci of pain could be found on orthopaedic or neurological examination. **A mild generalised lymphadenopathy** was also present.  3. **[Investigations:]** 1. **[Blood tests: ]** Firstly, blood was taken for **routine haematology** and **biochemistry**. This revealed a **mild** **neutrophilia**, indicating an **inflammatory response** and a **mild hypoalbuminaemia** (**21g/L**). The **low albumin** could represent a **negative acute phase response**, with the production of **acute** **phase proteins** causing a slight reduction in albumin, or there could also be a component of albumin loss or genuine liver disease. Bradley had no gastrointestinal signs and liver function was otherwise normal. **UPC** was mildly increased at **1.2**, suggesting some **urine protein loss** was present.  2. **[Imaging:]** Given the **pyrexia** and **generalised joint effusions**, screening radiographs of the **chest** and an **abdominal ultrasound** were performed to look for evidence of disease that could be triggering the high temperature and any process that might trigger immune-mediated joint disease (we'll explore this further in a moment). The screening imaging was normal.  Joint radiographs were taken.   The joint radiographs show **increased soft tissue opacities** over the joints, which is consistent with the **joint effusions** **palpable** on **examination**. The joint surfaces are smooth, which is consistent with a non-erosive polyarthritis. From the radiographic findings, which of the following disease processes is unlikely to be affecting Bradley? 1. A septic disease process 2. Correctly unselected 3. **Rheumatoid arthritis** Rheumatoid arthritis causes an erosive polyarthritis, so this is not likely to be causing disease in Bradley. A septic or immune-mediated process could be causing his polyarthritis. 3. **[Joint Taps:]**  After the radiographs were taken, joint taps were obtained from all four distal joints (both carpi and tarsi) and examined microscopically. What is the predominant cell type?  1. Eosinophils 2. Lymphocytes 3. Monocytes 4. **Neutrophils** Correct. Marked neutrophilic inflammation was revealed from all locations. There was no cytological evidence of bacteria and cultures were negative. Clinically, **sepsis** was also unlikely as it **usually affects a single joint**. If **multiple joints** are affected with **sepsis** then it can be **secondary** to a **septic** **focus** elsewhere (e.g. endocarditis), however animals will typically be **very unwell** with this and there was no evidence of signs of infection at other sites (brief echocardiography of the heart valves was normal and there was no murmur present).  Given the diagnostic findings, Bradley had an immune-mediated polyarthritis. Simon Tappin  Polyarthritis can be classified into four groups: 1. Type I: Truly idiopathic disease 2. Type II: Associated with distant infection (reactive arthritis) 3. Type III: Associated with gastrointestinal disease (rare in small animals but called an enteropathic arthritis) 4. Type IV: Associated with **neoplasia** (arthritis of malignancy) Gastrointestinal disease and neoplasia had been excluded by the screening imaging and there was no evidence of an infectious focus. Tick-borne disease had not yet been excluded as a differential. **Serology** for Borrelia (Lyme disease) revealed the presence of antibodies to the C6 Borrelia surface **protein** and **PCR** of the **joint fluid** was also **positive**, confirming Bradley had Borrelia or Lyme disease as the trigger to his immune-mediated polyarthritis. Which type of polyarthritis did Bradley have? - Type I - **Type II** - Type III - Type IV Bradley had Borrelia or Lyme disease as the trigger to his immune-mediated polyarthritis, which is classified as a type II polyarthropathy (reactive arthritis). \` 7. **[Lyme Disease:]** Lyme disease takes its name from the town of Lyme, found in USA state of Connecticut. Here, the symptoms of infectious polyarthritis were first described in people in the mid 1970's. Simon Tappin  Since then, the spirochaete *Borrelia burgdorferi sensu lato* has been found to be the causal agent of Lyme disease and it has been documented to cause disease in veterinary species. Most published research relates to* B.burgdorferi sensu stricto*, which is the **primary isolate** causing disease in the **USA**, however there is considerable genetic heterogenicity in* B.burgdorferi* species between **North** **America** and the **UK**. In **Northern Europe**, isolates of *Borrelia afzelii* and* Borrelia garinii *have also been found to cause borreliosis in people. Classic signs of canine Lyme disease occur following a tick bite and initial signs include **fever** and **lethargy**, followed by **shifting limb lameness**. Unfortunately, these classic signs are not always seen and are also seen in a wide range of other diseases, which can make the diagnosis of Lyme disease difficult.* B.burgdorferi *is also associated with **glomerulonephritis** and a **chronic non-erosive arthritis** which are both generally seen later in the course of the disease. Signs are usually seen within a month of the tick bite, however, in experimental studies, disease has taken up to 6 months to manifest. 4. **[Borrelia burgdorferi:]**  8. **[Clinical Signs:]** **Initial signs** of borreliosis are of **acute fever** (\>40˚C), **shifting limb lameness** and associated **lethargy**. There may also be **joint swelling** and **enlargement** of the **local lymph nodes**. These signs appear to be most severe in younger dogs and immunocompromised animals. Simon Tappin  - **Lameness** is usually first seen in the limb closest to the site of tick attachment and is thought to be caused by the **spread of spirochaetes** through the **skin**, **muscle** and **joint**. Classically the lameness improves over 2-3 days, at which point signs may resolve completely or appear in a different limb.  - In a proportion of dogs, a chronic non-erosive polyarthritis may develop. This is most likely in patients with a **chronic infection** which has been incompletely cleared by the immune system and represents an immune-mediated polyarthritis. Diagnosis of Borrelia as the trigger can be difficult (see below), however, prolonged treatment with antibiotics and in some cases descending **immunosuppressive doses** of steroids, will lead to an improvement in most patients.  - Protein-losing nephropathy (PLN) has been documented in dogs with spontaneous Borrelia infection. This so-called 'Lyme nephropathy' has not been documented in experimental models and the underlying pathophysiology is unclear. It has most commonly been reported in Northern America but has also been seen in the UK. Dogs develop glomerulonephritis, lymphocytic plasmacytic interstitial nephritis and tubular necrosis. As a result of the PLN, affected dogs develop **weight loss**, **lethargy** and **anorexia**, eventually leading to **renal failure**. About half of the dogs which develop Lyme nephritis have a **history of lameness**, with the signs of PLN being the first sign of Borrelia in many cases. - In people, a dramatic **"bull's eye" skin lesion** called erythema chronica migrans (ECM) develops in up to **90**% of people with Lyme disease. This classic bull's eye lesion is not seen often in dogs; however, a reddish rash can be seen for the first week or so after tick attachment. Neurological signs due to **meningitis**, **encephalitis** and **perineuritis** are seen occasionally in the later stages of infection in man. Although **focal meningitis** and **encephalitis lesions** have been documented in experimental models, neurological signs secondary to Borrelia in dogs are extremely rare. **Arrhythmia** secondary to Borrelia-induced myocarditis has been **occasionally** reported in dogs, which is similar to Lyme carditis seen in man. Simon Tappin  9. **[Diagnosis:]** A diagnosis of Lyme disease is challenging and is based on having **appropriate clinical signs**, **supportive laboratory data**, **exclusion** of other **possible differential diagnoses** and a **positive** **response to treatment**. 5. **[Differential Diagnosis:]**  **Haematological** and **biochemical changes** are **not pathognomonic** of borreliosis, although may support the presence of an **inflammatory response**. Signs of leukopenia or thrombocytopenia may suggest concurrent infection with a rickettsial pathogen such as Anaplasma phagocytophilum, as co-infection is relatively common. **Regular urinalysis** to monitor for PLN is suggested, with a **UPC ratio** being the best marker of **proteinuria**. **Joint taps** will have high numbers of **non-degenerate** **neutrophils** and an **increased protein content**. **Joint fluid** will have a **reduced viscosity** and should be **negative** on **bacterial culture**. During infection, *Borrelia *organisms change their **outer surface proteins (Osp)** to allow **transmission** and **increase** their chances of survival in the host. Initially, this is a change from the surface protein **OspA** to **OspC** and later **OspF**. The production of **OspC** is essential for spirochaete transmission and allows it to establish infection. Another **outer membrane protein** known as VIsE, or variable major **protein-like sequence**, rapidly changes its structure after infection, allowing rapidly **changing** **antigenic variation** and making it difficult for the host to produce antibodies which can **neutralise** the **infection**. The constant non-variable part of the **VIsE** (the **C6 peptide**), has been shown to correlate very well with the presence of* B.burgdorferi *infection, with measurable levels present **3-5 weeks after infection** and **declining rapidly after successful treatment**. **Positive serology** for **C6** **antibodies** allows rapid and definitive diagnosis of canine Lyme disease. Simon Tappin  Occasionally B.burgdorferi can be **visualised** in **body fluids** (e.g. synovial fluid) using **dark field** **microscopy**, or in **tissue** after silver or immunological stains; however, the spirochaete density is usually very low making diagnosis difficult by this method. **Culture** of Borrelia organisms is similarly difficult and as such, not clinically applicable. **Quantitative PCR tests** such as **real time PCR** have revolutionised diagnostics in many areas of veterinary medicine and the same is true of **canine Lyme disease**. A **variety** of **PCR tests** exist, however those with **primers to plasmid DNA** are **more sensitive** due to the **multiple copies** present within each bacterium. Although **blood** and **joint fluid** can be used for **PCR**, spirochaetes tend to invade through tissue rather than passive dissemination through the bloodstream, thus **tissue PCR** is **much more sensitive**. In particular, **PCR** of **synovial membranes** and **skin** has been shown to be **much more sensitive**, especially in the **later stages of the disease**.  Afbeelding met diagram Automatisch gegenereerde beschrijving  10. **[Knowledge Check:]** Culture of *Borrelia *organisms is difficult and therefore not clinically useful. - **True** - False PCR tests using blood or joint fluid samples are more sensitive than PCR tests on tissue samples. - True - **False** Levels of C6 antibodies remain high for a long time after the successful treatment of a B.burgdorferi infection. - True - **False** Positive serology for C6 antibodies gives a definitive diagnosis of canine Lyme disease. - **True** - False Dark field microscopy of body fluids to visualise *B.burgdorferi *is difficult as spirochaete density is usually very low. - **True** - False 11. **[Treatment:]** **Early** and **effective antibiotic therapy** has been shown to be very effective in reducing spirochaete numbers, leading to rapid improvement in the **signs** of **arthritis** over a 24-48 hour period. Simon Tappin  Doxycycline at **10 mg/kg SID or BID** is the drug of choice for the treatment of* B.burgdorferi*, although a number of other antimicrobials also have efficacy. Doxycycline is lipid soluble thus has **good tissue** and **cellular penetration**. Treatment is generally used for **4 weeks**, however, research has shown that not all dogs will clear the infection within this period and the recrudescence of infection can occasionally be seen. Doxycycline should not be used in growing animals due to its deleterious, but mainly cosmetic effects on the skin, nails and tooth enamel. Although doxycycline is less likely to cause these effects compared to other tetracyclines, alternative antibiotics such as amoxicillin are suggested for growing animals. In the UK, all of these antibiotics are used under the cascade, as there is not a licensed product for the treatment of canine Lyme disease. Doxycycline also has **immunomodulatory and chondroprotective effects**, which are helpful in the treatment of polyarthritis.  ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- **Drug** **Dose** **Route** **Interval (hours)** **Duration (days)** **Indications** ----------------------- ------------- ----------- ---------------------- --------------------- ----------------------------------------------------------------------------------------------------------------------------------------- Doxycycline (Ronaxan) 10mg/kg PO 12-24 30 Early disease, arthritis or neurological signs. Not for young animals. Always give with food or followed by water (especially in cats)  Amoxicillin 20mg/kg PO 8 30 Young patients Azithromycin 25mg/kg PO 24 10-20 Early disease Penicillin G 22,000 U/kg IV 8 14-30 Persistent disease Ceftriaxone 25mg/kg IV\ 24 14-30 Late neurologic or cardiac disease, persistent arthritis SC Cefotaxime 20mg/kg IV 8 14-30 Neurological manifestations Chloramphenicol 15-25mg/kg PO/SC 8 14-30 Neurological manifestations ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- If **proteinuria** is documented (and other causes of PLN excluded), early treatment for glomerulonephritis should be instigated alongside antibiotic therapy. Angiotensin-converting enzyme (ACE) inhibitors will **reduce renal protein loss** through an **altered glomerular filtration pressure**. Ultra-low aspirin therapy (0.**5mg/kg/BID**) is suggested to **prevent thromboembolism** as a result of **anti-thrombin loss** and **platelet dysfunction**. 12. **[Case-Example -- Bradley:]** Bradley was treated with doxycycline (**10mg/kg SID for 4 weeks**) and NSAIDs (meloxicam). Within 24 hours his temperature had normalised and he started to eat well. At this point, his walking was also a lot better and he was discharged home. There is a temptation to want to use steroids in immune-mediated polyarthritis cases, however, given the reactive nature of the disease in this dog, we elected to treat the cause of the arthritis and monitor him and his signs gradually improved. Simon Tappin The **proteinuria** was persistent but not dramatic and as serum albumin was always \>20g/l, this was not treated with an ACE inhibitor. The **UPC ratio** returned to normal over 6 weeks. This was likely a reactive glomerulonephritis **secondary** to the **infection** and given that it didn't progress, we felt it was unlikely to be Lyme nephritis. Lyme nephritis is uncommon in the UK but is seen in other parts of the world including the USA and Eastern Europe.  Bradley did very well and went on to make a full recovery. Afbeelding met hond, bruin, sneeuw, buitenshuis Automatisch gegenereerde beschrijving 13. **[Prevention:]** The best method of reducing the risk of Lyme disease is to **prevent** **ticks attaching**, or **killing** and **removing** them quickly when they do attach. Some molecules such as permethrin have a repellent effect against ticks, while others such as fipronil or the isoxazolines (e.g. afoxolaner) are fast acting acaricides. Simon Tappin   Regular use of an effective acaricide such as afoxolaner, fipronil and/or permethrin should be suggested to all owners of dogs walked in areas with high tick numbers, especially at high risk times of the year (autumn and spring). As spirochaete transmission does not occur until at least **24 hours after tick attachment**, prompt removal of the ticks within this period will stop transmission of Borrelia. As any acaricide will not be 100% effective in preventing tick attachment, owner vigilance and prompt tick removal using a tick hook will further reduce risks. A **vaccine (Merilym 3),** is also available to provide protection against borreliosis. The aim of vaccination is to induce antibody formation to the Borrelia surface proteins, with surface proteins OspA and OspB being the main antibody targets. **Vaccine-induced antibodies** enter the tick during **feeding**, once present, they are bactericidal and kill spirochaetes via complement-directed activity.  Although vaccination appears to be very effective, it is considered a **non-core vaccine** (see the WSAVA vaccine guidelines for more detail) and is generally only used in dogs in geographically at-risk areas and with a high degree of possible exposure (such as outdoor or hunting dogs).  ACVIM have recently updated their consensus statement on Lyme disease which includes more detailed discussion of the pro's and con's of vaccination, as well as how to overcome the challenge of identifying disease in vaccinated animals. Take a look below. Simon Tappin  **ACVIM consensus update on Lyme borreliosis in dogs and cats** 14. **[Pet Travel Scheme:]** Since the PETS travel scheme was introduced in 2000, the number of dogs and cats entering the United Kingdom has continued to grow quickly. In 2019, over 300,000 dogs made a crossing into the UK, a figure which has doubled in the 4 years since 2015 when only 164,836 dogs entered. The PETS scheme allows relatively free travel within qualifying countries once the PETS criteria have been met. Current requirements for PETS include a microchip, rabies vaccination and tapeworm treatment prior to entry or re-entry into the UK. Simon Tappin  The original aim of the PETS scheme was to reduce the risk of importing rabies, the zoonotic tapeworm *Echinococcus multilocularis* and tick vectors carrying diseases which were at the time not endemic to the UK. Following an amendment to the PETS scheme in 2012, it is no longer mandatory for tick treatment to be administered to travelling animals. Whilst PETS allows convenient travel, it does not contain requirements to reduce the risks of 'exotic' disease, so an increasing number of clinical cases are being encountered within the UK, some of which may ultimately become endemic.  15. **[Rabies:]** Quarantine requirements were introduced in the UK in 1897, primarily to control rabies. Rabies is still an important **zoonotic disease**, as once clinical signs develop it is invariably **fatal** and currently kills approximately 55,000 people each year, mostly in Asia and Africa. Simon Tappin  Rabies has an **incubation period of 2-3 months**, meaning that **initially infected animals appear normal**. **Quarantine** was therefore designed to hold imported animals in a secure area to see if clinical signs develop. The **6 month period of quarantine** is longer than the incubation period and ensures that if an animal is infected with rabies, its clinical signs are seen without the risk of rabies being spread throughout the country. This approach allowed the United Kingdom to become rabies free in 1922, with the last endogenous case of classical human rabies being recorded in 1902. In Europe, the main reservoir for infection comes from the fox population. Over the last two decades, **oral vaccine** laden bait programmes targeted at foxes and raccoon dogs have been very successful in reducing the incidence of rabies in **several western European countries**. As a result, several countries became rabies free (Italy in 1997, France in 2000, the Czech republic in 2004 and most recently, Germany and Austria in 2008). Unfortunately, subsequent importation of rabies infected dogs has threatened both France and Italy's rabies free status, highlighting the need for continued vigilance.    This marked reduction in rabies cases in Western Europe led the United Kingdom to re-examine its position on quarantine. In September 1998, Professor Kennedy chaired a government advisory group to reappraise the United Kingdom's position on rabies and **quarantine**. This group of eminent and independent experts concluded that pet travel to countries of the European Union would only lead to a marginal increase in risk of introducing rabies to the United Kingdom. The findings of this group, known as the **Kennedy report**, form the basis of the PETS scheme in place today.  The **PETS scheme** insists on animals being vaccinated against rabies, which further reduces the risks of animals bringing rabies into the United Kingdom. Vaccines give extremely good protection from rabies, however, as with any vaccine, a small number of animals do not mount an adequate response to be protected from the disease. This initially led to the requirement of a **vaccine titre** being measured **6 months before the animal could return to the United Kingdom**, however as modelling suggested a very low risk of rabies entering the UK, this requirement was subsequently withdrawn. Please note that requirements may change post-Brexit, follow the link for the most up to date information. **Pet travel to Europe post Brexit.** [**CLICK HERE(OPENS IN A NEW TAB)**](https://www.gov.uk/guidance/pet-travel-to-europe-after-brexit)  Rabies cases reported in Europe on the left hand side between 1990-2000 and on the right between 2000-2008 (courtesy of the Rabies Bulletin Europe www.who-rabies-bulletin.org) 16. **[Echinococcus multilocularis:]** The **PETS scheme** also requires that **animals are wormed** with praziquantel **24-48 hours prior** to **returning to the United Kingdom**, which is designed to **stop** the tapeworm* Echinococcus multilocularis *from entering. *Echinococcus multilocularis* is more commonly known as the fox tapeworm and is **endemic** in many parts of the world, including northern and central Europe.  Simon Tappin Its **life cycle** involves foxes and small herbivores such as voles, however dogs and cats can also be infected. Although* Echinococcus multilocularis *is of little clinical consequence to animals, aberrant infections in humans results in **alveolar echinococcosis**, which is an extremely debilitating disease with a high mortality rate. People become infected with *Echinococcus multilocularis *by **ingesting** **eggs** that are excreted by infected foxes, dogs or cats. These develop into the **larval stage** and initially form **small cysts** within the **liver**. However, over time (usually between 5 and 15 years), the **cysts enlarge** leading to clinical signs such as **jaundice**, **abdominal pain** and **weight loss**; left untreated this disease can be **fatal**. Distribution of Echinococcus multilocularis in Europe Distribution of Echinococcus multilocularis in Europe 17. **[So what diseases do we see with travel?:]** The requirements for **rabies vaccination** and the administration of praziquantel are to keep people in the UK safe, but there are no provisions for the protection of animals as they travel. Simon Tappin We need to give clear guidance to our clients, as depending on where they travel to, their pets will encounter lots of diseases that they will be completely naïve to. The ESCCAP website is a good place to direct owners for specific travel information, take a look at the link below. **ESCCAP - Travelling Pets** [**CLICK HERE(OPENS IN A NEW TAB)**](https://www.esccapuk.org.uk/travelling-pets-advice-owners/) We will discuss some of the common diseases we see in travelled pets over the next few lessons, so let's first have a look at their prevalence before finishing by looking at some of the more obscure, but nonetheless interesting imported diseases! Simon Tappin Tick-borne diseases have received a lot of interest recently, both in human and veterinary medicine. Ticks **have long life cycles** requiring them to feed on several different hosts at **different stages**, making them extremely efficient **vectors** **of disease**. Tick-borne diseases are tightly confined to the **area** of the tick vector, so increasing travel through the PETS scheme leads to increased exposure to unusual tick vectors and disease. Cases of Ehrlichia and Babesia were initially regularly reported through the DEFRA reporting scheme DACTARI.  -------------------------------------------------------------------------------------------------------------------------------------- **Disease** **\'01** **\'02** **\'03** **\'04** **\'05** **\'06** **\'07** **\'08** **\'09** **\'10** **\'11\ ** -------------- ---------- ---------- ---------- ---------- ---------- ---------- ---------- ---------- ---------- ---------- --------- Babesia   1 5 2 3 3 1 2 1 1       Ehrlichiosis     5   4   2 8 1   1 Dirofilaria         1   1       4 Leishmania 1 1 8 6 2 2 9 11 6   4 -------------------------------------------------------------------------------------------------------------------------------------- This scheme is no longer active and the figures reported poorly reflect the actual disease incidence, largely due to the scheme relying on voluntary reporting. 6. **[Nasal Mites:]** Local knowledge is very helpful if you are examining a dog that has travelled or been imported. Nasal mites (Pneumonyssoides caninum) are relatively common in **Scandinavia** and the **USA**, but are not seen in the UK (although one case has been reported in an untravelled dog visiting the coast in Scotland!). These mites cause nasal **irritation** and **reverse sneezing**, but usually respond well to treatment with selamectin. Take a look at the abstract below. **\ Pneumonyssoides Species Infestation in Two Pekingese Dogs in the UK.** [**CLICK HERE(OPENS IN A NEW TAB)**](https://pubmed.ncbi.nlm.nih.gov/18251989/)  7. **[Linguatula Serrata:]** Similarly unpleasant is Linguatula Serrata,also known "tongueworm" due to its appearance, a **worm**-**like parasite** which lives in the **nasal chambers**. Usually found in Eastern Europe and northern Africa, a number of cases have been seen recently in animals imported into the UK and it has been reported rarely within the UK fox population. Take a look at the abstract below.  **Nasal Infestation by Linguatula Serrata in a Dog in the UK: A Case Report ** [**CLICK HERE(OPENS IN A NEW TAB)**](https://pubmed.ncbi.nlm.nih.gov/28230234/) 18. **[Case Example- Pepper-Anne:]** Let's finish this lesson by looking at a final case. This is Pepper-Anne, an eight year old female neutered Australian Cattle Dog who had recently moved to the UK from an air force base in Arizona, USA. Simon Tappin   8. **[History:]** Pepper-Anne had a two week history of **cystitis** which cleared with antibiotics but returned when they were withdrawn. Imaging showed there were a **number of stones in the bladder** which were likely to be struvite, explaining the recurrent UTI, however, Pepper-Anne was also **lame**. This mostly affected the right forelimb and had been present for a number of months, gradually getting worse.  Radiographs of the forelimbs were taken. What can you see? Think about your answer before continuing. Simon Tappin    An extensive **permeative osteolytic lesion** involving the **mid to distal portion** of the **right radius** as well as the distal portion of the ulna was identified. Additionally, the accessory and radial carpal bones also revealed evidence of **osteolysis**. The lesions have led to marked **cortical thinning** of the **affected bones**. Well-defined **periosteal reaction** and **mild soft tissue** **swelling** was identified surrounding the **radius on the right side**. The **radiocarpal joint** also appeared moderately swollen. The left limb appears normal. **Radiographs** revealed **worsening** of **bone lysis** in comparison to that seen previously, with the main differential diagnoses being **fungal osteomyelitis** or **primary** **neoplasia**.  9. **[Bone Biopsy:]** A bone biopsy from the distal radius was performed to determine the underlying cause for the radiographic changes. Histology identified a **fungal infection**, with **extensive pyogranulomatous** **inflammation** leading to **bony lysis**. The **large size of the fungal organisms** and the **presence** of **multiple endospores** were suggestive of Coccidioidomycosis (a fungal infection present in Arizona).* Coccidioides immitis* is a **grade three** **pathogen** (capable of causing severe human disease), thus culture samples were submitted for **fungal culture** at the Health Protection Agency for speciation. The culture confirmed infection with *Coccidioidomycosis immitis*.  Given the swelling of the radiocarpal joint, joint fluid was retrieved via **arthrocentesis** for cytology to identify any **underlying infection** or **inflammation**. **Cytology** revealed a **low grade neutrophilic** **inflammation** but **no evidence of fungal hyphae**. Simon Tappin 19. **[Coccidioides immitis:]** *Coccidioides immitis* is a fungus only found in specific areas of the world (mainly the Southwest USA), where there is an adequate climate and environment for the fungus to grow. The **alkaline sandy soils** of **southwestern USA**, **western Mexico** and **Central** and **South America** are the normal habitat for Coccidioides fungal species, which grow as vegetative mycelia during **rainfall**. As a result of this geographical distribution, Coccidiomycosis is often referred to as Rift Valley Fever. At present, these conditions are not found in the United Kingdom, but occasional cases are imported into the country. Simon Tappin  The mycelia germinate and form arthrospores in dry soil conditions. These subsequently become airborne under appropriate weather conditions. In dogs and cats, the major route of infection is via **inhalation**. **Cutaneous contamination** by a penetrating wound occurs less commonly. Within the body, **arthrospores** transform into the spherules which undergo division, later rupturing at maturity to release hundreds of endospores. Each endospore that evades the host's immune response then enlarges into a new spherule and the life cycle starts again. The **severity** and **extent** of the disease depends on the host immunocompetence and ranges from a **mild pulmonic** form to **fatal multi-systemic dissemination**. Two species of Coccidioides have been identified, *Coccidioides posadasii* and *Coccidioides immitis*, which both have similar manifestations and drug susceptibilities. **Pulmonary infection** occurs via the **bronchioles** and **alveoli**, through the **peribronchial** **tissues** and to the **associated lymph** **nodes**. **Disseminated disease** extends beyond the **tracheobronchial** and **mediastinal lymph nodes** to the **axial** and **appendicular skeleton** and **overlying skin** (most commonly), **central nervous system**, **abdominal viscera**, **pericardium**, **myocardium** and **prostate**.  **[Direct transmission]** between infected patients has not been reported (in man or in veterinary species) and *Coccidioides immitis*is **not** generally regarded as a **zoonosis**. However, **inoculated** **infection** has the potential to occur in humans if sharps injuries occur during aspiration of infected tissues, surgery or post-mortem examination of infected veterinary patients. Hence proper **sedation** or **anaesthesia** and **protective wear** should always be used when taking **tissue samples** if an invasive fungus such as *Coccidioides immitis* is suspected. **Culture samples** can be submitted for fungal culture at the Health Protection Agency if Coccidioides infection is suspected. Material submitted for culture must be handled very carefully, especially when a tissue invasive fungal organism is suspected. **[Serological testing]** is also possible for *Coccidioides immitis *although only in the **USA**. **[Therapy]** of coccidioidomycosis includes the use of azoles or amphotericin-B. Treatment for a minimum of **4 -- 6 months** beyond clinical cure, with a marked reduction or resolution of positive serological findings is recommended. In the case of disseminated disease, treatment can be prolonged (often greater than one year) and in some cases, **lifelong therapy** is required. **Relapse** occurs commonly and it is unknown whether previous infection causes lifelong immunity as in humans.    Azoles inhibit ergosterol synthesis, resulting in cell **membrane permeability** and **inhibition** of fungal cell growth. Itraconazole (5mg/kg p.o q12h) is preferred for animals with **bony involvement**. Other potential azoles that could be used include ketoconazole and fluconazole. Ketoconazole is no longer the first drug of choice due to its **adverse effect** and **lower activity**. Fluconazole may be preferable for cases with **central nervous system** involvement. **Periodic monitoring** of **liver enzymes** is recommended with azole antifungal therapy due to possible **hepatotoxicity** (suggested after 4-6 weeks of therapy and then every 3-4 months). Treatment with Amphotericin-B should be reserved for **severe disease** failing traditional azole therapy. All azole drugs are potentially **teratogenic**, so they should be avoided in pregnancy and specific advice should be given to owners regarding their handling.  So whilst coccidioidomycosis and parasitic infections of the nose are rare, local knowledge and travel history taking are key to refining appropriate lists of differential diagnoses. In the next two lessons, we will learn more about the more commonly encountered diseases from pet travel, namely Babesia, Ehrlichia, Leishmania and Dirofilaria. 20. **[Completion of Online Learning:]** You have now completed Week Two, Lesson Two of Canine Infectious Diseases. Simon Tappin **To recap the learning objectives, you should now be able to:** 1. Explain why ticks are good vectors for disease using knowledge about their life cycles; 2. Recall the clinical signs associated with Borrelia (Lyme disease); 3. Outline how to make a diagnosis of Borrelia infection; 4. Consider the treatments options for Borrelia infection and the preventative options available; 5. Reflect on the PETS travel scheme and its impact on imported diseases.