Vol 54 4 Canine Monocytic Ehrlichiosis

8/18/2019 Vol 54 4 Canine Monocytic Ehrlichiosis

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VOLUME 54 (4) 1999

CANINE MONOCYTIC EHRLICHIOSIS – AN OVERVIEW

T. Waner1, A. Keysary

1, H. Bark

2, E. Sharabani

2 and S. Harruss

2

1. Israel Institute for Biological Research, P.O. Box 19, Ness Ziona 70400, Israel.

2. Koret School of Veterinary Medicine, Hebrew University of Jerusalem, P.O. Box 12, Rehovot 76100, Israel

Summary

Canine monocytic ehrlichiosis may be manifested by a wide variety of clinical signs. Therefore

clinicians, particularly those practicing in endemic areas, should always consider the possibility of

E. canis infection, especially when dogs are admitted with non-specific signs of illness. Owners

should be informed of the potential risk of tick-transmitted diseases in general and CME in

particular, and should be instructed to treat their pets against ticks on a regular basis.

Introduction

The etiologic agent of canine monocytic ehrlichiosis (CME), previously known as

canine rickettsiosis, canine hemorrhagic fever, tracker dog disease, canine tick

typhus, Nairobi bleeding disorder and tropical canine pancytopenia, is the

rickettsia Ehrlichia canis (1). It is a small-gram negative, coccoid bacterium that

parasitizes circulating monocytes intracytoplasmically in clusters called morulae

(2). Ehrlichia canis is mainly transmitted by the brown dog-tick Rhipicephalus

sanguineus (3, 4) and has also recently been shown to be transmittedexperimentally by the tick Dermacenter variabilis (5). The distribution of CME is

related to the distribution of the vector and has been reported to occur in Asia,

Africa, Europe and America (6, 7, 8). Infection occurs when the infected tick

ingests a blood meal and salivary secretions contaminate the feeding site. Once

the dog is infected the course of ehrlichiosis can be divided into three phases:

acute, subclinical, and chronic.

Clinical presentation: Naturally occurring CME may be manifested by a wide variety ofclinical signs (9). The clinical signs in the acute phase may occasionally be mild and nonspecificand may include depression! lethargy! mild weight loss! anore"ia! pyre"ia! lymphadenomegaly andsplenomegaly (#$). %ogs may present with bleeding tendancies! mainly petechiae and echymosesof the s&in and mucous membranes! and occasionally! epista"is may also occur. 'cular signs arenot uncommon! and include corneal opacity (due to edema andor deposition of cellular precipitates)! anterior uveitis! hyphema! tortuous retinal vessels and focal chorioretinal lesions

consisting of central pigmented spots with surrounding areas of hyperreflectivity (##). ubretinalhemorrhages! resulting in retinal detachment may occur and lead to blindness (#*).

Other clinical signs may include vomiting, serous to purulent oculonasal discharge, lameness,ataxia and dyspnea. Ticks are commonly found on dogs during this stage. In most cases, the

clinical signs will resolve without treatment, with dogs entering the asymptomatic subclinical


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phase (13, 14). Dogs that do not successfully eliminate the parasite during the subclinical stage

may remain in this stage and may subsequently proceed to the chronic phase of CME.

The common clinical signs of the chronic disease are weakness, depression, anorexia, chronic

weight loss and emaciation, pale mucous membranes, fever and peripheral edema, especially of the

hind limbs and the scrotum. Platelet-related bleeding, such as petechiae and echymoses of the skin

and mucous membranes and epistaxis are common findings (15, 16). Secondary bacterial and

protozoal infections, interstitial pneumonia, renal failure, and arthritis may occur during chronic

severe disease (17, 18). Some reproductive disorders have also been associated with chronic CME

including; prolonged bleeding during estrus, inability to conceive, abortion and neonatal death (1).

Polymyositis has also been associated with CME (19). Neurological signs may occur during the

acute and chronic disease. These include signs of meningoencephalitis, e.g. arched back, severe

neck or back pain, paraparesis or tetraparesis, ataxia, cranial nerve deficits and convulsions.

Neurological signs may be attributed to hemorrhages, vasculitis and extensive plasma cell

infiltration and perivascular cuffing of the meninges (20, 21, 22).

Experimental infection

In the clinical situation with naturally occurring cases, accurate staging of the disease is

difficult, if not impossible. In order to gain some understanding of the pathogenesis and clinical

course of the disease, studies have been carried out using artificially infected beagle dogs with E.

canis. The advantage of studying an experimental model lies in its ability to give information with

the minimal number of variables, which are inherent when studying dogs naturally infected with

any pathogen (23).

CME may manifest in a variety of clinical signs, which vary between and within different

geographical locations. Some of the reasons proposed include: ehrlichial strain variations (24, 25)

dose of infection, breed of dog, immunological status of the host and concurrent infections withother tick-borne parasites (26, 27, 28).

In contrast to the wide spectrum of clinical signs encountered in natural infections, artificial

infection of naive beagle dogs with an Israel strain of E. canis (#611) has been shown to reveal a

relatively uniform pattern in the development of the disease (23). Six male adult beagles negative

for E. canis antibodies by the immunofluorescent antibody (IFA) test were injected with

heparinized blood from a longstanding infected beagle dog. The first antibodies

Pathogeneis: The pathogenesis of a disease may be related to the cytopathic effects of theorganism itself, the reaction of the body to the infecting organism, or a combination of both.

However, in the case of CME, it appears to be related mainly to an excessive immunological

reaction of the dog to the rickettsial agent. Pathological changes in naturally infected dogs includeextensive plasma cell infiltration of parenchymal organs, perivascular cuffing particularly of the

lungs, kidneys, spleen, meninges and the eyes, positive Coombs’ and autoagglutination tests (29).

Clinical pathological evidence for an immunopathological etiolology for CME lies in the

development of hypergammaglobulinemia in infected dogs, usually polyclonal in nature, and seen

typically in the acute phase of the disease. The level of anti-E. canis antibodies is not correlated

with the concentration of the serum gammaglobulins (30).

Further evidence for an immunopathological disease mechanism was demonstrated in

experimental infection studies carried out on splenectomized dogs (31). Intact and splenectomized

dogs were infected with an Israeli strain of E. canis and serology, clinical signs and hematological

parameters were examined over a period of 60 days. During the acute phase, the splenectomized

dogs appeared subjectively less depressed and sick, showing less severe effects on both bodytemperature and food consumption compared with the intact dogs. Comparison of hematological


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parameters between the intact and the splenectomized groups revealed less prominent

hematological changes in the latter. The results suggested the involvement of immune

mechanisms in the pathogenesis of CME, and that the spleen plays a major role in its pathogenesis.

The typical lymphoplasmacytic splenitis with the resultant liberation of splenic inflammatory

mediators and/or other splenic substances, has been proposed to play a key role in pathogenesis

(31).

The development of typical thrombocytopenia has also been attributed to an

immunopathological mechanism. Significant levels of serum antiplatelet IgG antibodies have been

demonstrated in E. canis artificially-infected dogs 17 days PI (32). At this stage the dog has

already developed a significant thrombocytopenia. However, the initial decrease in thrombocyte

numbers appeared to occur within a few days of infection: already on day 3 post-infection mean

circulating platelet counts had already decreased by 11% of the preinfection values. The very early

decline in platelet numbers can be explained by the premature appearance of antiplatelet antibodies

within a few days after infection resulting in the removal of antibody-coated platelets by the

mononuclear phagocyte system in the liver and spleen. It was hypothesized that E. canis infection

in dogs altered the immune system resulting in overproduction of natural antiplatelet antibodies of

increased affinity (33). It was proposed that the presence of antiplatelet antibodies is one of the

major causes of thrombocytopenia seen in CME, although other non-immunologically mediatedmechanisms may also be involved.

Diagnosis: %iagnosis of CME is based on anamnesis! clinical presentation and

confirmation by laboratory tests. +resently the indirect immunofluorescent

antibody (,-) test is the most acceptable serological test! although dotblot

en/yme lin&ed immunoassay (E0,) procedures developed and were shown to

be sensitive for the detection of antibodies to E. canis (12! 13! 14). The presence

of antiE. canis antibody titers at a dilution greater than #52$ is considered positive

(#6). ,n the acute stage of the disease titers may increase rapidly. ,n areas

endemic to other Ehrlichia species! crossreactivity between E. canis and E.

ewingii! E. e7ui or E. risticii should be ta&en into consideration (16). Cross

reactivity between E. canis and Neoric&ettsia helminthoeca (the etiologic agent of

salmon poisoning disease) has also been documented (18). There is no serologic

crossreaction between E. canis and E. platys (19).

Microscopic demonstration of typical intracytoplasmic E. canis morulae in monocytes is

occasionally seen during the acute stage of the disease and is diagnostic of the disease. Therefore,

blood and buffy-coat smears should be carefully evaluated. However, only 4% of blood smears of

dogs with ehrlichiosis reveal typical E. canis morulae (40). Other methods used mainly for

research purposes for diagnosis of E. canis infections are culturing the parasite, polymerase chainreaction (PCR) and Western immunobloting (41, 38). A study comparing PCR, culturing the

parasite, IFA and Western immunobloting in early detection of the parasite has shown that cell

culture reisolation method proved to be the most sensitive and definitive for early diagnosis. It is

not however a convenient method, as it requires 14 to 34 days to give positive results (41). It was

concluded from experimental studies, that the use of the E. canis serum soluble antigen for early

diagnosis of acute CME is limited, as the first detection of the soluble antigen appears

inconsistently and only after the appearance of anti-E. canis antibodies (42).

Diagnosis of subclinical disease should be based on anamnesis, geographic location of the dog,

persistent antibody titers to E. canis, mild thrombocytopenia and hypergammaglobulinemia (14).

The diagnosis of subclinical disease is a challenge to the practicing veterinarian (43). Theimportance of early diagnosis lies in the relatively good prognosis before the animal enters the


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chronic phase, at which stage the prognosis is grave. The chronic disease is the end-stage of the

disease process and its diagnosis is based on the anamnesis, the typical severe pancytopenia,

antibody titers to E. canis and serum hypergammaglobulinemia and a lack of response to antibiotic

therapy. This stage is usually easier to diagnose.

Treatment: %o"ycycline (#$mg&g! once daily! for a period of at least three

wee&s) in conunction with ,midocarb dipropionate (3mg&g! two inections at #2

day interval! ,M) is considered the treatment of choice for CME (9). %o"ycycline

is fre7uently used alone where ,midocarb is unavailable or not approved for use.

hort term treatment with do"ycycline (#$mg&g! once daily! for 6 days) has been

shown to result in failure (22). lthough previous studies have shown the in vivo

efficacy of imidocarb in the treatment of CME (23! 24)! a recent in vitro study has

indicated that it may be ineffective (26).

Other drugs with known efficacy against E. canis include tetracycline hydrochloride (22mg/kg, q 8hrs), oxytetracycline (25mg/kg, q 8 hrs), minocycline (20mg/kg, q 12 hrs) and chloramphenicol

(50mg/kg, q 8 hrs) (48). Supportive treatment should include multi-vitamin supplementso. In

severe cases blood transfusions should be given.

There is increasing evidence that immunological mechanisms are involved in the pathogenesis of

the disease. Thus, the use of immunosuppressive doses of glucocorticosteroids in treatment of the

acute stage of CME should be considered (23).

When demonstrating other Rhipicephalus-borne parasites such as Hepatozoon canis or Babesia

canis, in blood smears, co-infection with E. canis should always be considered as co-infections are

common (49, 50). Co-infections with E. platys, which is presumably transmitted by Rhipicephalus

sanguineus, are also common (39, 51). Concurrent infections of E. canis and Borrelia burgdorferior Leishmania donovani have been documented, indicating also the possibility of co-infections

with other parasites that are not transmitted by the brown dog tick (52, 53). After treatment, anti-E.

canis antibody titers may persist for months and even for years (54). It has been shown that

persistence of E. canis antibody titers post treatment was related to the initial titer at the time of

treatment (54). The persistence of high antibody titers for extended periods, after prolonged

treatments may represent an aberrant immune response (54), or treatment failure. After successful

treatment, sero-positive dogs are susceptible to rechallenge (55). A progressive decrease in the

gammaglobulin concentrations was associated with elimination of the parasite (55). Prognosis of

the acute phase of CME is good if treated appropriately. The prognosis of the subclinical stage is

good to guarded, as this phase is asymptomatic, however these animals are at risk of developing

the chronic stage of the disease. The prognosis of the chronic stage is poor to grave in dogs with

pancytopenia.

Prophylaxis: To date! no effective antiE. canis vaccine has been developed and

tic& control remains the most effective preventive measure. ,n endemic areas! low

dose o"ytetracycline treatment (4.4 mg&g) once daily has been suggested as a

prophylactic measure (34). :ecently this method has been used with success by

the -rench army in dogs in enegal! ,vory Coast and %ibouti (36). %ogs were

treated prophylactally with *3$mg per os per day! and the estimated failure rate

was found to be $.9;. %espite the success of the treatment! the authors do not

consider it practical due to the possibility of the future development of resistantstrains of E. canis. This would ma&e treatment of dogs more complicated and as a


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redecrease the rate of successful treatment. s there is no intermediate host in the

pathogenesis of CME! ric&ettsia may be transmitted by contaminated blood

transfusions. Therefore! blood donors and transfusions should be screened

regularly.

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from the International Conference on Rickettsiae and Rickettsial Diseases & American Society for Rickettsiology 14th sesquiannual

joint meeting. Marseilles-France 13-16 June. 1999.

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Vol 54 4 Canine Monocytic Ehrlichiosis