Ehrlichiosis

Ehrlichiosis is caused by several bacterial species of the genus Ehrlichia. Ticks like the Brown Dog tick (Rhipicephalus sanguineus), the Lone Star tick (Amblyomma americanum) and the American Dog tick (Dermacentor variabilis) are the main transmitters of these pathogens. Although the clinicopathologic course of the disease will vary depending upon the infecting Ehrlichia species, illness is typically characterised by an acute reduction in cellular blood elements, most often thrombocytopenia.

Canine monocytic ehrlichiosis (CME) is caused by Ehrlichia canis and characterised by three clinical phases. The infectious agent is widely distributed in warm climates and causes severe clinical symptoms in infected dogs. The life cycle of E. canis implicates ticks as vectors and mammals as host. Generally all members of the family Canidae can serve as host whereas ticks like the Brown Dog tick and in the USA presumably also the American Dog tick, are the main transmitters of the pathogen.

Historical synonyms for canine ehrlichiosis include canine rickettsiosis, canine typhus, tropical canine pancytopenia, idiopathic hemorrhagic syndrome, canine hemorrhagic fever and tracker dog disease.

In humans, human monocytic ehrlichiosis (HME) is caused by Ehrlichia chaffeensis. The disease possesses zoonotic character. Furthermore Ehrlichia ewingii has also been isolated from a human patient and thus is as well of zoonotic potential. In the USA, the disease occurs primarily in the south-eastern and south-central regions of the country, however due to chronic infection and a prolonged incubation period, infection is frequently documented in dogs that move from endemic to non-endemic regions.

Pathogens

Ehrlichia spp. are gram-negative, small, obligatory intracellular bacteria that primarily invade leukocytes of animals and humans. They appear as minute, round bacteria (cocci), about 1 µm in diameter. In the leukocytes, ehrlichiae divide by binary fission, developing from elementary to initial bodies to finally form vacuole-bound colonies known as morulae (plural for morula, Latin word for mulberry, referring to the mulberry-like clustering of the dividing organisms). The formation of morulae is a defining characteristic of this group of bacterial pathogens.

The pathogens are transmitted by vectors in which they replicate. In the Ehrlichia canis genogroup, these vectors are generally ticks.

Transmission electron microscopical image of morulae of ehrlichiae in a bone marrow leukocyte from a human ehrlichiosis patient.
Transmission electron microscopical image of morulae in a bone marrow leukocyte of a human ehrlichiosis patient. Arrows indicate individual ehrlichiae.

Classification

In the order Rickettsiales the family Anaplasmataceae contains four genera of medical importance: Ehrlichia, Anaplasma, Neorickettsia and Aegyptianella.

The genus Ehrlichia nowadays comprises the species Ehrlichia canis, Ehrlichia chaffeensis, Ehrlichia ewingii, Ehrlichia muris and Ehrlichia (Cowdria) ruminantium. These species are united into the ‘E. canis genogroup’. Members of the Ehrlichia genus are implicated as pathogens of dogs, cats, ruminants, horses and humans.

 

Ehrlichial agents known to infect dogs and cats 

Species Common name of disease(s) Common natural host(s) Cells most commonly infected Primary vector(s) Distribution Clinical Disease (*Human Disease)
Ehrlichia Canis

 

Canine monocytic ehrlichiosis (CME)

Dogs, wolves, jackals (members of the family Canidae) (humans)

Primarily mononuclear cells (monocytes, macrophages, lymphocytes)

Rhipicephalus sanguineus, (Dermacentor variabilis)

Worldwide, primarily tropical and temperate climates

Dogs: fever, lethargy, thrombocytopenia, anorexia, myalgia, lymphadenopathy, bleeding diatheses

Cats: fever, lethargy, anorexia

*identified in Venezuela

Ehrlichia chaffeensis

Human monocytic ehrlichiosis (HME)

Humans, dogs, deer (horses, rodents)

Monocytes, macrophages, lymphocytes

Amblyomma americanum, Dermacentor variabilis

USA, Europe, Africa, South and Central America

Dogs: mild/subclinical unless present in co-infection

Cats: not reported

*Human monocytic ehrlichiosis

Ehrlichia ewingii

Canine granulocytic ehrlichiosis (CGE) (mild form), human granulocytic ehrlichiosis (HGE)

Dogs (humans)

Primarily neutrophils and eosinophils

Amblyomma americanum, Otobius megnini

USA

Dogs: fever, polyarthritis, thrombocytopenia, neurologic disease

Cats: not reported

*Granulocytic ehrlichiosis, uncommon

Ehrlichia (Cowdria) ruminantium

Heartwater disease

Ruminants

Endothelial cells, moncytes, macrophages, neutrophils

Amblyomma spp.

Africa, Caribbean

Dogs: subclinical/rare

Cats: not reported

a from Allison & Little (2013)

 

Ehrlichia canis is responsible for the widespread canine monocytic ehrlichiosis (CME) in tropical and temperate areas of the world. The geographical distribution of E. canis has expanded with the distribution of its tick vector, the Brown Dog tick, Rhipicephalus sanguineus.

Ehrlichia chaffeensis primarily infects mononuclear leukocytes (predominantly monocytes and macrophages), but may also be seen occasionally in the granulocytes of some patients with severe disease. It is the agent of human monocytic ehrlichiosis (HME). Ehrlichia chaffeensis could be detected by PCR in naturally infected dogs that were sick or healthy at the time of testing.

Microscopic image of Ehrlichia sp. morulae in the cytoplasm of a monocyte.
Ehrlichia sp. morulae in the cytoplasm of a monocyte

Ehrlichia ewingii primarily infects neutrophils and occasionally eosinophils and produces a disease clinically similar to HME and HGA (human granulozytic anaplasmosis). Most patients with ehrlichiosis caused by E. ewingii also had other medical conditions causing immunosuppression. In the USA, this pathogen generally causes a milder form of disease referred to as canine granulocytic ehrlichiosis (CGE). Infection with E. ewingii frequently induces polyarthritis in dogs and occasionally causes neurological disease in dogs and human patients.

Microscopic image of Ehrlichia sp. morula in the cytoplasm of a neutrophil.
Ehrlichia sp. morula in the cytoplasm of a neutrophil

Ehrlichia (Cowdria) ruminantium is the agent of heartwater disease in ruminants in Africa and the Caribbean. Based upon PCR amplification and DNA sequencing, E. ruminantium has been found in blood samples from dogs and HIV-infected humans in South Africa.

 

Human pathogenic Ehrlichiae

Recently several Ehrlichia spp. have been recognized as emerging human pathogens. Human monocytic ehrlichiosis (HME) is caused by E. chaffeensis, and E. ewingii, which was previously known as a canine pathogen, has also been recognized as human pathogen. Additionally an asymptomatic infection of a human patient in Venezuela was associated in molecular biological examinations with E. canis. Furthermore an E. ruminantium-like organism was recently found in humans and deer in the southeastern USA. Generally, with the exception of E. muris, all may be human pathogens.

 

Further pathogenic Anaplasmataceae

Another genus of medical importance of the family Anaplasmataceae is Neorickettsia. Besides a relevant human pathogen species (Neorickettsia sennetsu), the species Neorickettsia risticii and Neorickettsia helminthoeca have been reported to cause clinical signs in dogs, and antibodies have been detected in the sera of dogs and cats among others. In cats the former only caused clinical signs experimentally, while in the latter no feline disease is reported.

Epidemiology

Canine monocytic ehrlichiosis (CME) due to Ehrlichia canis is a widespread disease in tropical and temperate areas of the world, like in the USA, Europe (Mediterranean) and Africa. The geographical distribution of E. canis has expanded with the distribution of the primary tick vector, the Brown Dog tick, Rhipicephalus sanguineus, which spends all three stages of its life cycle on dogs.

Ehrlichia chaffeensis and Ehrlichia ewingii have been diagnosed in dogs only within the USA. Both species are encountered most frequently in dogs living in the southern states. Meanwhile they have also been reported from Africa and Asia (Korea).

 

Natural reservoirs of Ehrlichiae

The Brown Dog tick is the known main vector of E. canis. In the USA the American Dog tick (Dermacentor variabilis) is also suspected as an additional vector, but epidemiological importance is unclear. Canines, both wild and domestic, are susceptible and represent reservoirs for the organism.

The Lone Star tick, Amblyomma americanum, is the most important vector for E. chaffeensis and E. ewingii in the USA. Deer serve as a major reservoir for both of these organisms and transmission to dogs and humans is more likely in areas that support a large deer population. For E. chaffeensis, the American Dog tick (D. variabilis) is also reported as vector.

As transovarial transmission in ticks is not confirmed for E. canis so far, ticks are not considered as true reservoir, whereas mammals are representing a reservoir. Especially in infected dogs, E. canis might persist for years.

The zoonotic role of dogs as a reservoir for human infection has not been clearly established for any Ehrlichia species. In South America, E. canis has been reported to cause human monocytic ehrlichiosis (HME) with dogs as the probable reservoir host. Besides deer, rodents and other small mammals may serve as major reservoirs for the other Ehrlichia species, with dogs playing only a minor role in the maintenance of the organism in a given geographic location.

Transmission

Transstadial transmission of Ehrlichia canis occurs within the Brown Dog tick, Rhipicephalus sanguineus, whereas transovarial transmission has not been confirmed so far. All tick stages can be infected while feeding on infected dogs. Subsequently these ticks drop off, moult and acquire another canine host. Ticks can obtain E. canis only if engorgement occurs during the acute phase of the disease in dogs.

Nymphal and adult Brown Dog ticks are capable of transmitting E. canis for at least 155 days following detachment from the infected host. If the tick acquires an uninfected host and harbours a sufficient number of organisms, infection of the new host may occur. It has been demonstrated on dogs and in vitro that transmission of E. canis by R. sanguineus starts quickly after tick attachment, already within hours (Fourie et al., 2013).

In the American Dog tick, Dermacentor variabilis, experimental transmission of E. canis to nymphs and experimental transmission from infected D. variabilis adults to the host was successful. The tick is suspected as additional vector in the USA, but epidemiological importance is unclear.

Finally, Ehrlichia spp. infection may also be introduced in susceptible dogs by blood transfusion.

Pathogenesis

Ehrlichiae are obligate intracellular bacteria which attack white blood cells, a feature even more specialized at the species level:

  • Ehrlichia canis infects canine monocytes and lymphocytes but only rarely infects neutrophils;
  • Ehrlichia ewingii infects canine granulocytes;
  • Ehrlichia chaffeensis infects predominantly monocytes and macrophages.

 

The elementary body is the infective stage and enters the monocyte or other leucocyte types by phagocytosis. Elementary bodies are individual ehrlichiae 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 leads to the formation of the morula, the configuration that typifies the genus. Rupture of the host cell releases the elementary bodies to infect new cells. The organisms are progressively dividing and spreading throughout the body via mononuclear cells. In later stages thrombocytopenia and eventually irreversible bone marrow destruction are observed.

Diagnosis

Ehrlichiae infections pose difficult diagnostic challenges to both clinicians and laboratorians. Therefore, treatment decisions should be based on epidemiologic and clinical clues, and should never be delayed while waiting for confirmation. Fundamental understanding of the signs, symptoms, and epidemiology of the disease is crucial in guiding requests for tests for ehrlichiosis and interpretation of testing results.

 

Laboratory tests

Routine clinical laboratory tests indicative of ehrlichiosis include low white blood cell count, low platelet count, and elevated liver enzymes. Therefore, pancytopenia, aplastic anaemia or thrombocytopenia would be consistent with Ehrlichia canis infection. The organisms can be demonstrated in smears of blood, buffy coat, bone marrow aspirates and spleen aspirates by staining with Diff-Quik or Giemsa. But light microscopic evidence of the pathogens is only successful during the acute phase of the disease and is strongly influenced by the type of material used. Laboratory confirmation of ehrlichiosis requires serologic, molecular, or culture-based methods.

Microscopic image of a Diff-Quik stain of Ehrlichia chaffeensis in DH82 cells using 1000-times magnification.
Diff-Quik stain of Ehrlichia chaffeensis in DH82 cells, 1000X

Serology

Serologic diagnosis remains useful for evaluating patients for evidence of infection. Tests like the indirect immunofluorescent antibody test (IFAT) provide a high sensitivity, but no opportunity to differentiate between current acute or chronic infection or previous infection in which the organisms were immunologically or therapeutically eliminated. Another disadvantage is the cross reactivity with different Ehrlichia species and thus a low specificity.

Commercially available test systems detecting antibodies to specific peptides of E. canis are commonly used, but may also show cross-reactivity with other Ehrlichia species. Although developed for use in dogs, these assays are not species specific; the tests may be used for identifying antibodies to Ehrlichia spp. also in cats (Little, 2010).

Dogs generally become seronegative within 3 to 9 months after effective treatment, although some dogs maintain persistent and stable titres for years.

When antibodies to Ehrlichia spp. are identified in an apparently healthy dog, blood tests including a complete blood count with a platelet count should be performed to evaluate for the presence of subclinical disease that may indicate treatment is needed (Little, 2010).

Microscopic image of an immunofluorescent antibody test of Ehrlichia chaffeensis in DH82 cells using 400-times magnification.
IFAT of Ehrlichia chaffeensis in DH82 cells, 400X

Molecular detection

Second to serologic methods, amplification of ehrlichial DNA by polymerase chain reaction (PCR) is the most frequently used method for detecting infection or to confirm the therapeutic elimination. EDTA blood is required for PCR and should optimally be collected prior to or after cessation of antibiotics.

 

Isolation and cultivation 

Direct isolation of the organism remains the gold standard for confirmatory diagnosis, showing a high sensitivity, but is the most difficult and time-consuming approach. The disadvantages of the technique are the high costs, the high laboratory standard needed and especially the time until the result is available (14-34 days). Thus the method is not useful as routine test.

Clinical Signs

Disease manifestations caused by members of the Ehrlichia canis genogroup (Ehrlichia canis, Ehrlichia chaffeensis, Ehrlichia ewingii) infecting dogs and eventually cats can be indistinguishable, and there can be strain variation in pathogenicity. Based upon experimental infection studies, canine ehrlichiosis has been divided into three phases: an acute, a sub-clinical and a chronic disease phase. Nevertheless, onset and duration of infection is rarely known in the clinical setting.

The acute phase follows an incubation period of 1 to 3 weeks and is characterized by fever, anorexia, weight loss, oculonasal discharge, lymphadenopathy as well as thrombocytopenia, leukopenia, low anaemia and hypergammaglobulinaemia. During this phase, the organisms are dividing and spreading throughout the body via mononuclear cells. Other clinical signs include: depression, severe loss of stamina, dyspnea and oedema of the limbs and the scrotum. A variety of central nervous system signs, including hyperesthesia, muscle twitching and cranial nerve deficits may occur due to inflammation and bleeding into the meninges. Clinical findings in the acute phase of canine ehrlichiosis can be identical to anaplasmosis, canine Rocky Mountain spotted fever or canine distemper. The acute phase usually resolves spontaneously within one or two weeks, even without appropriate treatment.

After 2 to 4 weeks, the subclinical phase develops without clinical symptoms and with a low thrombocytopenia, lasting for 40 to 120 days or even years, during which the animals are persistently infected. Immunocompetent animals may successfully eliminate the pathogen during this period. Other animals may develop the so-called chronic stage of infection with severe and life-threatening clinical manifestations.

The chronic phase is characterised by varying degrees of depression, fever and weight loss. A combination of bleeding tendencies, pallor due to anaemia, abdominal tenderness, anterior uveitis, retinal haemorrhages and neurological signs consistent with meningoencephalitis, typify dogs that are chronically affected. Irreversible bone marrow destruction and polysystemic immune complex disease mark the later stages of the chronic phase. Additionally the situation is often complicated by secondary bacterial infection.

Immunosuppression has been historically attributed to infection with E. canis in dogs; however, an experimental infection study did not induce detectable immunosuppression. Furthermore, epistaxis, once considered a hallmark of the disease, occurs infrequently in dogs (in the USA) and may be attributable to concurrent infection with a Bartonella species or other infectious agents.

Ehrlichiosis is more severe in certain dog breeds (e.g. German shepherd) and in younger animals. However, co-infection, immune status and strain variation could all play a role in determining the types of disease manifestations and the severity of pathology in the individual canine patient.

Dogs with clinical disease due to E. ewingii most commonly present with fever and lameness associated with a neutrophilic polyarthritis; neurologic signs, including ataxia, head tilt, and paresis are also reported (Goodman et al., 2003). In contrast, experimental infection with E. chaffeensis alone generally produces mild disease (Dawson & Ewing, 1992; Zhang et al., 2003).

In cats disease due to Ehrlichia spp. appears rare compared with that in dogs. The most common clinical presentation is described as fever, lethargy, and anorexia, here usually associated with E. canis and not E. chaffeensis or E. ewingii.

Treatment & Prevention

Tetracycline or doxycycline, administered daily for four weeks, represent the treatment of choice for canine ehrlichiosis. Fever generally subsides within 24-72 hours after treatment. In fact, failure to respond to a tetracycline antibiotic in dogs with acute or mild chronic phase argues against a diagnosis of ehrlichiosis.

Severe chronic or complicated disease may require longer treatment course: Haemorrhage, immunosuppression, or concurrent infections with Babesia, Bartonella or Leishmania species may contribute to the death of chronically affected dogs, despite the tetracycline therapy. Supportive therapy, including fluids, blood transfusion, vitamins, and anabolic steroids are required in some patients.

Often no elimination of the pathogen is achieved, especially when animals have not been treated during the acute phase, but later during the subclinical or chronic phase. Nevertheless dogs with chronic infection still have a good prognosis if treatment has been performed for one month and no further concurrent disease or infection is worsening the clinical state during treatment. Following the therapeutic elimination of the organism, dogs do not develop protective immunity and can be reinfected when reintroduced to a pathogen-competent tick.

A vaccination is not available at the moment so that the only current way of prevention is a tick prophylaxis and control.

As Ehrlichia canis has been shown to be transmitted by Rhipicephalus sanguineus ticks starting already within a few hours after attachment, there is a strong need for acaricides to provide either a repellent, an anti-attachment and/or a rapid killing effect against ticks in order to decrease the risk of transmission of E. canis (Fourie et al., 2013).

References

Pathogens

Allison RW, Little SE: Diagnosis of rickettsial diseases in dogs and cats. Vet Clin Pathol. 2013, 42, 127–44

 

Transmission

Fourie JJ, Stanneck D, Luus HG, et al.: Transmission of Ehrlichia canis by Rhipicephalus sanguineus ticks feeding on dogs and on artificial membranes. Vet Parasitol. 2013, 197, 595-603

 

Diagnosis

Little SE: Ehrlichiosis and anaplasmosis in dogs and cats. Vet Clin North Am Small Anim Pract. 2010, 40, 1121-40

 

Clinical Signs

Dawson JE, Ewing SA: Susceptibility of dogs to infection with Ehrlichia chaffeensis, causative agent of human ehrlichiosis. Am J Vet Res. 1992, 53, 1322-7

Goodman RA, Hawkins EC, Olby NJ, et al.: Molecular identification of Ehrlichia ewingii infection in dogs: 15 cases (1997-2001). J Am Vet Med Assoc. 2003, 222, 1102-7

Zhang XF, Zhang JZ, Long SW, et al.: Experimental Ehrlichia chaffeensis infection in beagles. J Med Microbiol. 2003, 52, 1021-6

 

Treatment & Prevention

Fourie JJ, Stanneck D, Luus HG, et al.: Transmission of Ehrlichia canis by Rhipicephalus sanguineus ticks feeding on dogs and on artificial membranes. Vet Parasitol. 2013, 197, 595-603

Further Reading

Breitschwerdt EB, Hegarty BC, Hancock SI: Sequential evaluation of dogs naturally infected with Ehrlichia canisEhrlichia chaffeensisEhrlichia equiEhrlichia ewingii, or Bartonella vinsonii. J Clin Microbiol. 1998, 36, 2645-51

Little SE: Ehrlichiosis and anaplasmosis in dogs and cats. Vet Clin North Am Small Anim Pract. 2010, 40, 1121-40

Neer TM, Breitschwerdt EB, Greene RT, et al.: Consensus statement on ehrlichial disease of small animals. J Vet Intern Med. 2002, 16, 309-15 

Nicholson WL, Allen KE, McQuiston JH, et al.: The increasing recognition of rickettsial pathogens in dogs and people. Trends Parasitol. 2010, 26, 205-12

www.cdc.gov/ehrlichiosis/

 

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