Anaplasmosis

Anaplasmosis is caused by several bacterial species of the genus Anaplasma. From their reservoir hosts (e.g. mice, deer, possibly birds) the bacteria are transmitted by ixodid ticks like the Castor Bean tick (Ixodes ricinus), the Deer tick (Ixodes scapularis), the Western black-legged tick (Ixodes pacificus) and the Brown Dog tick (Rhipicephalus sanguineus). In general, anaplasmosis leads to milder disease than monocytic ehrlichiosis caused by Ehrlichia canis and appears to be largely a self-limiting infection in dogs.

Anaplasma phagocytophilum is the most important representative and has been detected in blood samples from a wide range of wild and domestic animals. It can cause an acute febrile illness e.g., granulocytic anaplasmosis in dogs, cats and horses. In humans, the pathogen is responsible for human granulocytic anaplasmosis (HGA), formerly known as human granulocytic ehrlichiosis (HGE).

Pathogens

Anaplasma phagocytophilum is an obligate, intracellular, gram-negative bacterium with a size of 0.2-2.0 µm and of coccoid shape. It is the cause for the widespread granulocytic form of canine anaplasmosis in temperate zones of the world. Former synonyms for this disease have been “tick-borne fever” or “pasture fever”. In Europe, the predominant vector is the Castor Bean tick (Ixodes ricinus), while the Deer tick (Ixodes scapularis) and the Western black-legged tick (Ixodes pacificus) are the main transmitting vectors in North America. Due to a spread of ixodid ticks, the geographical distribution of A. phagocytophilum is expanding to northern regions, like South Scandinavia. Besides dogs, A. phagocytophilum can be detected in a wide range of mammals, including cats, horses, sheep, goats, cattle, wild animals and humans.

Anaplasma platys (former Ehrlichia platys) causes canine cyclic thrombocytopenia in tropical and warm regions of the world, like the Mediterranean, Asia, Middle East, Africa, Australia, and the USA. The Brown Dog tick (Rhipicephalus sanguineus) and Dermacentor spp. are thought to transmit the pathogen. A. platys are the only rickettsia known to infect platelets. The organisms appear as round, oval or bean shaped blue cell inclusions in platelets and range from 0.35 to 1.25 µm in diameter.

 

Classification

Anaplasma species are closely related to the genus Ehrlichia. Both genera belong nowadays to the family Anaplasmataceae, in the order Rickettsiales. Species of the genus Anaplasma are implicated as pathogens of dogs, cats, ruminants, horses and humans.

 

Important veterinary and human species of the family Anaplasmataceae

Species Common name of diseases(s) Common natural host(s) Cells most commonly infected Primary vector(s) Distribution
Anaplasma bovis Bovine ehrlichiosis Cattle

Monocytes, macrophages,

erythrocytes

Haemaphysalis spp.,

Ixodes spp.,

Hyalomma spp,.

Rhipicephalus (Boophilus) spp.

Asia, Africa, South America
Anaplasma phagocytophilum (formerly Ehrlichia phagocytophila, Ehrlichia equi and HGE-agent)

Canine anaplasmosis

Tick-borne fever, 'pasture disease', benign ovine rickettsiosis

Human granulocytic anaplasmosis (HGA)

Equine ehrlichiosis

Dogs

Cattle, goats, sheep, wild ruminants  

 

Humans

Horses

Neutrophils (eosinophils, monocytes)

Ixodes ricinus (Europe),
I. scapularis, I. pacificus (North America),

Dermacentor silvarum,
I. persulcatus (Asia, Russia),

I. trianguliceps, I. hexagonus, I. ventalloi (Europe),

Hyalomma longicornis

moderate and temperate areas/ many countries of northern hemisphere (Europe and America), Asia, Africa
Anaplasma platys (formerly Ehrlichia platys) Canine cyclic thrombocytopenia Dogs Platelets

Rhipicephalus sanguineus

(Dermacentor spp.)

Southern USA, Australia, Southern Europe (Mediterranean), South America, Asia, Middle East,  Africa
Ehrlichia canis Canine monocytic ehrlichiosis (CME) Dogs, wolves, jackals (members of the family Canidae) (humans) Primarily mononuclear cells (monocytes) Rhipicephalus sanguineus, (Dermacentor variabilis) Worldwide, primarily tropical and temperate climates
Ehrlichia chaffeensis Human monocytic ehrlichiosis (HME) Humans, dogs, deer (horses, rodents) Monocytes, macrophages, neutrophils, lymphocytes Dermacentor variabilis USA, Europe, Africa, South and Central America
Ehrlichia ewingii Canine granulocytic ehrlichiosis (CGE) (mild form), human granulocytic ehrlichiosis (HGE) Dogs (humans) Primarily neutrophils and eosinophils

Amblyomma americanum,

Dermacentor variabilis,

Rhipicephalus sangineus,

(putative vector: Otobius megnini)

USA
Ehrlichia muris Not currently associated with disease Rodents, humans Mononuclear cells Haemaphysalis spp. Japan
Ehrlichia ondiri Ondiri disease, bovine petechial fever Cattle, sheep Granulocytes Unknown Africa
Ehrlichia (Cowdria) ruminantium Heartwater disease Ruminants Endothelial cells Amblyomma spp. Africa, Caribbean
Neorickettsia helminthoeca Salmon poisoning disease Dogs, foxes, coyotes Macrophages, monocytes Infected trematodes (Nanophyetus salmincola) in salmons USA
Neorickettsia risticii Potomac horse fever, equine monocytic ehrlichiosis;
atypical syndrome of monocytic ehrlichiosis in dogs
Horses (dogs, cats, coyotes, pigs, goats) Monocytes, mast cells, enterocytes Infected trematodes in snails and aquatic insects USA, Canada, (France, India)

Neorickettsia sennetsu

Sennetsu fever, glandular fever Humans Monocytes, macrophages Presumably infected trematodes in fish Japan, Malaysia

 

 

The closely related genus Ehrlichia was initially grouped according to the type of blood cells most commonly infected (granulocyte, lymphocyte, monocyte, platelet), and disease classes have been termed "granulocytic (or granulocytotropic) ehrlichiosis" or "monocytic (or monocytotropic) ehrlichiosis". However, this way of classification was misleading because some of the Ehrlichia species have been found in cells other than their main target cell type. In addition, more than one species may be responsible for the broad category of "monocytic" or "granulocytic" ehrlichiosis. Thus, the former classification was changed (as mentioned in the table above).

Epidemiology

Canine anaplasmosis is a widespread disease.

Anaplasma phagocytophilum infections in dogs as well as in humans have been detected in many countries of the Northern hemisphere. For Europe, e.g., in Denmark, Germany, Austria, Poland, Portugal, Great Britain, France, Italy, Norway, Slovenia, Switzerland and Sweden infections in mammals (and ticks) have been reported. Due to a spread of ixodid ticks, the geographical distribution of A. phagocytophilum is expanding to northern regions, like South Scandinavia. Also in the USA, South America and Asia the disease was detected. Small mammals, especially rodents, as well as deer and birds, are supposed to be the reservoir.

Anaplasma platys, which causes canine cyclic thrombocytopenia, is more frequently found in warmer regions than A. phagocytophilum. The pathogen has been detected in tropical and warm regions of the world, like the Mediterranean, the Middle East, regions of Asia, Africa, Australia, and the USA. The Brown Dog tick (Rhipicephalus sanguineus) and Dermacentor spp. are thought to transmit the rickettsial pathogen.

Transmission

Anaplasmae are transmitted by tick vectors of different species. The Castor Bean tick, Ixodes ricinus, is the main vector for Anaplasma phagocytophilum in Central and Northern Europe, while the Deer tick (Ixodes scapularis) and the Western black-legged tick (I. pacificus) are the main transmitting vectors in North America. Anaplasma platys is transmitted by the Brown Dog tick (Rhipicephalus sanguineus) and Dermacentor spp. 

Pathogenesis

Anaplasma phagocytophilum is an obligate intracellular bacterium which primarily attacks neutrophil granulocytes but also eosinophils of different species, including dog, cat, cattle, sheep, goat, horse, deer, rodents and birds. Monocytes and lymphocytes act as secondary host cells.

The elementary body is the infective stage and enters the host cell by phagocytosis. Elementary bodies are individual bacteriae about 1 µm in diameter and usually coccoid or ellipsoid in shape. Once they are captured inside the phagosomes, the pathogens replicate by binary fission, forming clusters of tightly packed elementary bodies termed initial bodies. Additional growth and replication lead to the formation of microcolonies, so called morulae, the configuration that typifies the genus. Apoptosis of the host cell causes a dissolving of the morulae so that the bacteria are released to the blood and are able to infect new cells. Furthermore bacteria can also be released by exocytosis too.

Anaplasma phagocytophilum infection is associated most commonly with the development of mild to moderate thrombocytopenia, also other cytopenias may occur, including neutropenia, lymphopenia, and mild anaemia.

The pathogenic impact of Anaplasma platys in dogs is not clearly defined. The species infects platelets leading to abnormalities of primary haemostasis. Differences in severity of illness have been described depending on the geographic origin of the A. platys strain. As only a few experimental studies have been performed, it could be suggested that the clinical variability could be due to other factors like immune status, stress conditions, breed, etc. Furthermore, the common detection of A. platys in dogs co-infected especially with Ehrlichia canis may lead to misunderstanding of the real pathogenic impact of the infectious agent.

Diagnosis

The diagnostic criteria for confirmed human granulocytic anaplasmosis are clinical signs and laboratory findings suggestive of granulocytic anaplasmosis together with

  1. detection of morulae within neutrophils (rarely eosinophils) on blood smears combined with a single positive reciprocal antibody titre to Anaplasma phagocytophilum (or a positive PCR result),
  2. a 4-fold increase or decrease in the antibody titre within 4 weeks,
  3. a positive PCR test result using specific A. phagocytophilum primers,
  4. isolation of A. phagocytophilum from blood.

These criteria can also be applied to dogs and other species, however, isolation is not used routinely for diagnosis.

Antibody testing can be performed by IFAT (indirect immunofluorescence antibody test) or ELISA (enzyme-linked immunosorbent assay). Since the seroprevalence is high in endemic areas, a diagnosis cannot be based on a single positive titre (which may only reflect previous exposure). During acute illness, antibodies may be inapparent. A four times or higher increase in antibody titres is essential to confirm the diagnosis. Paired serum specimens taken at least two to three or more weeks apart are considered to be most helpful for evaluation (Center for Disease Control, USA).

Cross reactions of antibodies do occur to some extent with other Anaplasma, Ehrlichia and Neorickettsia species.

Conventional and real-time PCR assays have been developed for detection of A. phagocytophilum DNA in peripheral blood, buffy coat, bone marrow, cerebrospinal fluid or splenic tissue. The targets of the assays have been either the 16S rRNA gene, or the outer surface protein genes such as msp2. Assays based on the msp2 gene are usually specific for A. phagocytophilum , whereas assays based on the 16S rRNA gene may detect other Anaplasma species or even other bacteria. PCR may pick up infection when microscopy has appeared negative. In experimentally infected dogs, PCR tests on whole blood were positive for 6-8 days before and 3 days after morulae appeared on blood smears.

A diagnosis of Anaplasma platys may be made by detecting organisms within platelets on stained blood films or buffy coat smears (e.g. Giemsa or Diff-Quik). Due to cyclic parasitaemia the pathogen could either be absent or present in very low numbers. Thus this method is not reliable. An IFAT for detection of serum antibodies is available (likely cross-reacts with A. phagocytophilum) and different PCR-based assays have been developed.

Clinical Signs

In general anaplasmosis leads to milder disease in dogs than ehrlichiosis caused by Ehrlichia canis, but with similar clinical signs. To date, no fatal case has been reported in dogs. 

After an incubation period of 10 to 14 days (for Anaplasma phagocytophilum infection) clinical signs develop, including fever (>39°C), anorexia, depression, lethargy, splenomegaly, rarely lymphadenomegaly or hepatomegaly. In some animals, reluctance to move, weakness and lameness occur as well as gastrointestinal and respiratory signs.

Haematological abnormalities in dogs with anaplasmosis include thrombocytopenia, which is the most consistent laboratory abnormality, but also anaemia, lymphopenia or lymphocytosis, both neutrophilia and neutropenia as well as monocytosis and monocytopenia. Biochemical findings include hypoalbuminaemia, hyperglobulinaemia, elevated plasma alkaline phosphatase or hyperbilirubinaemia.

Infection with A. phagocytophilum appears to be self-limiting in dogs. The extent to which the pathogen induces chronic infection is unknown. Experimentally infected dogs have developed a persistent A. phagocytophilum infection for months. Although development into a chronic disease is less likely in comparison to E. canis infection, recrudescence of anaplasmosis can occur if the animal is subsequently immunosuppressed in the months after the infection occurred.

Signs of Anaplasma platys infection include fever, anorexia, lethargy, primary haemostatic disorders as the pathogen destroys platelet cells of the host, mild anaemia, and lymphadenomegaly. Bacteraemia and subsequent thrombocytopenic episodes (with platelet counts below 20,000/µl) recur at 1- to 2-week intervals. Co-infection with E. canis may lead to severe diseases.

Treatment & Prevention

Testing of antiinfective susceptibility of Anaplasma phagocytophilum showed doxycycline, rifampin, and levofloxacin to be the most effective.

The treatment of choice for granulocytic anaplasmosis in dogs is doxycycline. Most dogs show clinical improvement within 24 – 48 hrs of antibiotic treatment.

Following the therapeutic elimination of the organism, dogs do not develop protective immunity and can be reinfected when exposed again to a pathogen infected tick. Reinfection has not been reported in dogs so far, in human medicine one case has been documented. Horses have been shown to resist infection after recovery from initial infection with A. phagocytophilum.

Anaplasma platys infections have been successfully treated by the application of tetracyclines (e.g., doxycycline, enrofloxacin).

As in all vector transmitted diseases, an effective and consistent vector control is one of the key measures to prevent transmission of the pathogen and thus disease. In the case of anaplasmosis this is achieved by an effective tick control in form of application of acaricidals, ideally with repellent efficacy.

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