28 Jul 2016
Get the latest independent information canine rickettsial diseases, tick-borne diseases that multiply within circulating cells.
Simon Tappin
Job Title
Rhipicephalus tick. Image: Smith1972/Shutterstock.com
Image: Smith1972/Shutterstock.com
European and RCVS recognised specialist in Veterinary Internal Medicine
Medicine Consultant, Dick White Referrals, Six Mile Bottom, Cambridgeshire, UK
Hon. Assoc. Professor of Small Animal Medicine, University of Nottingham
Canine rickettsial diseases include Ehrlichia and Anaplasma infections and occur in many parts of the world. They are tick-borne diseases that multiply within circulating cells, with different infectious agents having different target cells and clinical signs associated with deficiencies and dysfunction of these specific cell lines.
Ehrlichia canis is endemic in southern Europe and is transmitted by Rhipicephalus sanguineus. Infection leads to acute disease, associated with fever and lethargy. Many dogs recover; however, some develop chronic disease with marked pancytopenia, leading to associated clinical signs such as bleeding disorders and severe anaemia. Treatment with doxycycline in the acute phase is generally successful, but chronic infection is associated with a much graver prognosis.
Anaplasma phagocytophilum is transmitted by Ixodes ticks and leads to vague clinical signs of anorexia and listlessness with pyrexia, joint swelling and lymphadenomegaly commonly reported. Treatment with doxycycline is usually successful.
Key words: Ehrlichia, Anaplasma, rickettsial disease, ticks, doxycycline
Rickettsiae are intracellular organisms causing disease by affecting the function of their target cells, which are mainly white cells and platelets (Table 1), leading to signs associated with deficiencies and dysfunction of those cell lines.
Rickettsiae are classified within α-proteobacteria and include the genera of Ehrlichia (which includes Ehrlichia canis) and Anaplasma (which includes Anaplasma phagocytophilum).
Nomenclature of rickettsial disease can be confusing as recent advances in DNA sequencing allowed reclassification of the order Rickettsiales in 2001, leading to some organism’s names being changed.
Also, historically, individual organisms have been named by the genus of the infectious agent, the species it affects and its predominant target cell (for example, Ehrlichia canis leading to canine monocytotrophic ehrlichiosis), whereas with the advent of molecular testing, the genus and species responsible can be much more easily defined, creating less confusion as to the responsible infectious agent.
The genera of Ehrlichia and Anaplasma are tick-borne diseases and limited to the geographic location of the vector. Ehrlichia canis is the most common of the rickettsial diseases seen in southern Europe, but is not currently considered endemic in the United Kingdom, whereas Anaplasma phagocytophilum has been isolated in Ixodes ticks within the United Kingdom and rarely associated with clinical disease.
Ehrlichia canis, the causal agent of canine monocytotrophic ehrlichiosis, is a small, pleomorphic gram negative intracellular rickettsial parasite that appears as round intracytoplasmic inclusions within monocytes and macrophages.
Ehrlichia canis infects dogs and wild canids, including the jackal, fox and coyote. It was first described in Algeria in 1935, but did not gain prominence until the Vietnam War when many American service German shepherd dogs, which are highly susceptible to Ehrlichia canis infection (or tropical canine pancytopenia as it was known at the time), died as a result of the disease.
It also received publicity when confused as the cause of human monocytotrophic ehrlichiosis in the late 1980s until Ehrlichia chaffeensis was discovered as the cause.
Ehrlichia canis infection is found worldwide in temperate and tropical areas, with the exception of Australia. The areas where canine Ehrlichia canis infection is reported mirror the geographic distribution of its vector Rhipicephalus sanguineus (the brown dog tick).
In Europe, accurate information on disease prevalence is not available; however, cases are particularly concentrated around the south coast of France, Corsica and Greece, and the southern half of Italy (Figure 1).
Although Ehrlichia canis is not currently considered endemic in the United Kingdom, dogs are occasionally imported with the disease and recent cases in untravelled dogs have been reported (Wilson and others, 2013). The route of infection in these dogs is unknown; they had neither knowingly mixed with dogs that had travelled abroad nor had a recent history of tick attachment.
Rhipicephalus sanguineus is not endemic to the United Kingdom as climatic conditions are too cold; however, numbers are increasing due to importation, and Defra acknowledges a risk of establishment within houses (Toth and Roberts, 2011, Jameson and others, 2010).
There has also been suggestion that Ehrlichia could become established in other tick species, for example Argas vespertilionis, which is a tick associated with bats in Europe (Socolovschi and others, 2012).
The reservoir for Ehrlichia canis infection is in wild and domestic dogs. Its vector Rhipicephalus sanguineus has a single host preference and feeds on dogs at all three stages of its life cycle. Experimentally, the American dog tick Dermacentor variabilis has also been shown to transmit infection. Ehrlichia canis is passed to the next stage but is not passed on transovarially in the tick so unexposed ticks must feed on an infected dog in the acute phase to become infected. After attachment, Ehrlichia transmission may be rapid, with experimental studies showing this can occur as early as three hours post exposure (Fourie and others, 2013).
Once infected, the incubation period is reported as 8-20 days and the organism spreads throughout the body multiplying in macrophages. Three phases of ehrlichiosis are seen: acute, subclinical and chronic.
The acute phase usually lasts one to four weeks and most dogs recover with appropriate treatment. Typically, non-specific signs such as fever, anorexia and lymphadenomegaly are reported. Haematology usually reveals thrombocytopenia, leucopenia and anaemia. Untreated dogs or those that do not fully clear the organism may enter a subclinical state where they become asymptomatic carriers for months to years.
Persistently infected dogs may spontaneously clear Ehrlichia; however, in some dogs the organism persists, leading to chronic infection. Not all dogs develop the signs of chronic disease and why this occurs is not clear, but it appears more common in German shepherd dogs.
The spleen and its mononuclear phagocytic system appears important in determining pathogenesis, and in experimental animals, splenectomised dogs show less severe clinical signs.
Chronic infection leads to bone marrow hypoplasia and resultant pancytopenia. Thrombocytopenia and platelet dysfunction leads to severe bleeding in some cases (sub-mucosal haemorrhage and epistaxis).
The prognosis associated with chronic Ehrlichia canis infection is very guarded. In this phase biochemistry will usually reveal a marked increase in globulins. This increase in globulins is usually polyclonal, although occasional monoclonal increases have been reported, and hyperviscosity associated with clinical signs such as retinal detachment have occasionally been seen.
Identification of Ehrlichia morulae in leucocytes is diagnostic, but can be difficult and is time consuming. Blood collected from a peripheral capillary vessel, for example from the ear margin, or buffy coat analysis, are most rewarding. Morulae have also been reported within macrophages in lymph node and lung aspirates.
Serology is widely used, with immunofluorescence antibody titres >40-80 considered evidence of exposure. Using serology, a rising titre of a fourfold increase over a two-week period confirms active infection. Several commercial ELISA tests are also available and are useful for patient-side use.
Cross reaction and therefore false positive results can occur if there is exposure to less pathogenic rickettsiae; however, this is much less of a problem in Europe than in the United States. Diagnosis can be made on the basis of PCR, which is very sensitive and is effective at confirming that animals have cleared the infection after treatment.
Doxycycline (Ronaxan®) is the treatment of choice (10mg/kg q24hrs for 28 days*) and generally leads to a clinical improvement within one to three days.
Imidocarb has been suggested for use in resistant infections; however, experimental work has shown it to be ineffective at clearing Ehrlichia canis infection (Eddlestone and others, 2006). Chloramphenicol should be used in these instances (25-50mg/kg q8hrs po for 21-28 days). Chloramphenicol has also been suggested in puppies younger than five months of age due to the risk of tetracyclines leading to enamel staining of teeth.
Supportive treatment with fluid therapy and blood transfusions may be required, depending on the patient. Short-term use of steroids should also be considered if there is a life-threatening thrombocytopenia, as it is likely that immune mediated destruction is part of its pathogenesis.
Pancytopenia (especially in the presence of severe anaemia), prolonged activated partial thromboplastin time and hypokalaemia have been shown to be associated with a poor prognosis (Shipov and others, 2008).
The effects of feline Ehrlichia are not well documented, although Ehrlichia-like organisms have been seen in sick cats in several countries, including France, Spain and Italy.
Clinical signs include fever, joint pain, anaemia, dyspnoea and lymphadenopathy (Breitschwerdt and others, 2002). Doxycycline (Ronaxan® 10mg/kg q24hrs for 28 days*) is suggested as first line treatment, followed by imidocarb, if this is unsuccessful.
* Longer duration of treatment, based on a benefit:risk assessment by the responsible veterinarian, may be required in severe and chronic ehrlichiosis.
Anaplasma phagocytophilum, previously named Ehrlichia phagocytophilum, Ehrlichia equi and Cytoecetes phagocytophila, leads to granulocytic ehrlichiosis. First reported in Scottish sheep in the 1930s, it was reported as the cause of pasture fever in cattle in England in the 1950s and in Finland a decade later.
The first canine cases were reported in the 1980s in Switzerland, Sweden and North America, and feline cases in Sweden in the late 1990s.
Anaplasma is transmitted by several species of Ixodes ticks, with transmission of the organism thought to occur within 24-48 hours of attachment (Figure 2).
A low prevalence (0.74%) of Anaplasma phagocytophilum has been found in Ixodes ticks in the United Kingdom (Smith and others, 2013). Clinical cases are occasionally reported both in the United Kingdom (Bexfield and others, 2005) and other temperate parts of Northern Europe. Ixodes ticks that harbour Anaplasma may also co-infect with other organisms, such as Borrelia burgdorferi.
Anaplasma phagocytophilum is an obligate intracellular organism and infects mainly granulocytes. Its complete pathogenesis is unknown; however, it appears within cytoplasmic inclusions, which can be seen in circulating neutrophils for 7-14 days post infection.
Clinical signs vary between geographic strains and are usually seen after an incubation period of 4-14 days. Initial signs are usually vague, with anorexia and listlessness commonly reported.
Clinical examination often reveals pyrexia, lameness with associated joint stiffness and swelling, and lymph node enlargement. Neurological signs secondary to meningitis are more commonly seen with Anaplasma infection compared to Ehrlichia.
Diagnostic evaluation may reveal Anaplasma inclusion bodies within neutrophils, accompanied by mild to marked neutropenia and thrombocytopenia. PCR for Anaplasma performed on whole EDTA blood is commonly available and more sensitive than direct microscopy.
Treatment with doxycycline (10mg/kg q12hrs po for 10-21 days – note Ronaxan® is not licensed for treament of Anaplasma) is usually successful. Steroidal therapy may need to be considered if immune-mediated disease is present.
Anaplasma platys (previously known as Ehrlichia platys) has a tropism for platelets and leads to canine cyclic thrombocytopenia. It was first reported in the United States in 1978 and since then has been reported in much of the world including southern Europe and the Mediterranean basin, Southeast Asia, South America, Africa and Australia.
Although its mode of transmission has not been fully detailed, it is believed to be transmitted by Rhipicephalus sanguineus, which is supported by its geographical distribution and reported co-infection with Ehrlichia canis, although this has not yet been definitively proven by experimental transmission studies.
Anaplasma platys morulae appear as small round or oval inclusions within platelets and appear at their highest concentrations around 8-15 days after experimental infection. This is followed by a period of profound thrombocytopenia, with the platelet counts often dropping below 20×109/l as a result of direct injury to the platelets and the associated immune response, recovering to normal over three to four days.
Cyclical episodes of thrombocytopenia then occur at 7-14-day intervals. The levels of parasitaemia becoming less marked over time; however, the thrombocytopenia is often marked suggesting an immune-mediated mechanism during later episodes.
There is geographic variation in strains of Anaplasma platys and therefore differences in reported clinical signs by area.
In the United States minimal clinical signs post infection are reported; however, in the Mediterranean area severe cyclical episodes of bleeding such as epistaxis have been reported. Co-infection with Babesia canis or Ehrlichia canis may lead to more pronounced clinical signs.
Diagnosis is usually made by microscopic detection of the organism; however, serology and PCR tests are also available. Treatment with doxycycline (10mg/kg q12hrs po for 10 days – note Ronaxan® is not licensed for treatment of Anaplasma) or enrofloxacin (5mg/kg q24hrs po for 21 days) have been shown to clear infection.
The best method of reducing the risk of rickettsial disease is to prevent ticks attaching, or killing and removing ticks quickly when they do attach. Some molecules, such as permethrin, have a repellent effect against ticks while others, such as the isoxazolines (e.g. afoxolaner), are fast-acting acaricides.
As Anaplasma infection is thought to take 24-48 hours to be transmitted after tick attachment, prompt removal in this period will help reduce the risk of infection. However, for Ehrlichia canis it may be less effective as transmission can occur very rapidly after tick attachment.
Regular use of effective tick products 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).
Since any acaricide will not be 100% effective in preventing tick attachment, owner vigilance and prompt tick removal using a tick hook will further help to reduce the risk of tick-borne disease transmission (Figure 3).
Ronaxan® contains doxycycline. Indications: Treatment of respiratory tract infections in cats and dogs, including rhinitis, tonsillitis, bronchopneumonia and feline respiratory disease. Treatment of arthropod-borne Ehrlichia canis infection in cats and dogs. For information about side effects, precautions, warnings and contra-indications, please refer to the product packaging and package leaflet. Legal category POM-V (UK), POM (Ireland). Ronaxan® is a registered trademark of Merial. For further information refer to the datasheet or contact Merial Animal Health Ltd, CM19 5TG, UK. ©Merial Ltd 2016. All rights reserved.
Use medicines responsibly.
