VOLUME  54 (4) 1999

CANINE MONOCYTIC EHRLICHIOSIS – AN OVERVIEW

T. Waner1, A. Keysary1, H. Bark2, E. Sharabani2 and S. Harruss2

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

  Introduction     Clinical presentation    Experimental infection    Pathogenesis    Diagnosis    Treatment   

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 transmitted experimentally 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. 

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Clinical presentation: Naturally occurring CME may be manifested by a wide variety of clinical signs (9).  The clinical signs in the acute phase may occasionally be mild and non-specific and may include depression, lethargy, mild weight loss, anorexia, pyrexia, lymphadenomegaly and splenomegaly (10). Dogs may present with bleeding tendancies, mainly petechiae and echymoses of the skin and mucous membranes, and occasionally, epistaxis may also occur. Ocular signs are not uncommon, and include corneal opacity (due to edema and/or deposition of cellular precipitates), anterior uveitis, hyphema, tortuous retinal vessels and focal chorioretinal lesions consisting of central pigmented spots with surrounding areas of hyper-reflectivity (11). Subretinal hemorrhages, resulting in retinal detachment may occur and lead to blindness (12).

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 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).             

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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 with other 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 the organism 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 include extensive 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 body temperature and food consumption compared with the intact dogs. Comparison of hematological 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 mediated mechanisms may also be involved.

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Diagnosis: Diagnosis of CME is based on anamnesis, clinical presentation and confirmation by laboratory tests. Presently the indirect immunofluorescent antibody (IFA) test is the most acceptable serological test, although dot-blot enzyme linked immunoassay (ELISA) procedures developed and were shown to be sensitive for the detection of antibodies to E. canis (34, 35, 36). The presence of anti-E. canis antibody titers at a dilution greater than 1:40 is considered positive (17).  In the acute stage of the disease titers may increase rapidly. In areas endemic to other Ehrlichia species, cross-reactivity between E. canis and E. ewingii, E. equi or E. risticii should be taken into consideration (37). Cross-reactivity between E. canis and Neorickettsia helminthoeca (the etiologic agent of salmon poisoning disease) has also been documented (38). There is no serologic cross-reaction between E. canis and E. platys (39).

    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 chain reaction (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). The importance of early diagnosis lies in the relatively good prognosis before the animal enters the 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.

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    Treatment: Doxycycline (10mg/kg, once daily, for a period of at least three weeks) in conjunction with Imidocarb dipropionate  (5mg/kg, two injections at 14 day interval, IM) is considered the treatment of choice for CME (9). Doxycycline is frequently used alone where Imidocarb is unavailable or not approved for use. Short term treatment with doxycycline (10mg/kg, once daily, for 7 days) has been shown to result in failure (44).  Although previous studies have shown the in vivo efficacy of imidocarb in the treatment of CME (45, 46), a recent in vitro study has indicated that it may be ineffective (47).

Other drugs with known efficacy against E. canis include tetracycline hydrochloride (22mg/kg, q 8 hrs), 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 burgdorferi or 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 anti-E. canis vaccine has been developed and tick control remains the most effective preventive measure. In endemic areas, low dose oxytetracycline treatment (6.6 mg/kg) once daily has been suggested as a prophylactic measure (56).  Recently this method has been used with success by the French army in dogs in Senegal, Ivory Coast and Djibouti (57).   Dogs were treated prophylactally with 250mg per os per day, and the estimated failure rate was found to be 0.9%.  Despite the success of the treatment, the authors do not consider it practical due to the possibility of the future development of resistant strains of E. canis. This would make treatment of dogs more complicated and as a redecrease the rate of successful treatment. As there is no intermediate host in the pathogenesis of CME, rickettsia may be transmitted by contaminated blood transfusions. Therefore, blood donors and transfusions should be screened regularly.

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