Cause

Canine monocytic ehrlichiosis (CME) is an important tick-borne disease of dogs caused by the rickettsial organism Ehrlichia canis. It is transmitted by the Ixodidae tick Rhipicephalus sanguineus, the “brown dog tick,” found throughout the United States with noted prevalence in the southeastern, midwestern, and northeastern states. Other identified tick-borne rickettsial organisms that can infect the dog and cause similar clinical disease are Ehrlichia ewingii, Anaplasma phagocytophilum, Neorickettsia risticii, Anaplasma platys, and Ehrlichia chaffeensis. E. chaffeensis, the causative agent of human monocytotropic ehrlichiosis, can cause a milder form of disease in naturally infected dogs.

The known tick vectors for E. chaffeensis are Amblyomma americanum and Dermacentor variabilis, and E. chaffeensis also must be considered as a cause of canine ehrlichiosis. Distribution of infected ticks that carry E. chaffeensis has been reported in the south-central, southeastern, mid-Atlantic states, and California. In a large serosurvey conducted in the United States, antibodies to Ehrlichia spp. possibly induced by exposure to either E. canis or E. chaffeensis were more common in the southern states (Bowman et al, 2009).

Clinical Findings

Clinical signs of CME ehrlichiosis are multisystemic and can be mild to severe depending on the stage of disease. The German shepherd is considered particularly sensitive and susceptible to the severe form of CME. The varied presentations may be categorized into one of three stages: acute, subacute, and severe chronic. Most reports of the acute form of clinical disease are within 10 days postinfection or postexposure to ticks. The acute stage in most dogs is mild and may go undetected by the owner because only mild elevations in temperature, lethargy, and weight loss may occur. Overt signs of bleeding can occur and usually are due to thrombocytopenia or thrombocytopathia; petechiae, ecchymoses, and epistaxis are most common. Other clinical signs are uveitis, polymyositis, polyarthritis, and central nervous system signs, which may include seizures, ataxia, vestibular deficits, and cerebellar dysfunction. The granulocytic Ehrlichia spp. (E. ewingii; A. phagocytophilum [previously E. equi]) most commonly have been associated with polyarthritis. Recently a report of a German shepherd dog with severe acute hepatitis was determined to be associated with E. canis infection (Mylonakis et al, 2010). Apparently, many dogs exposed to E. canis seroconvert but never show clinical signs. It is unknown why they maintain high antibody titers. Do they truly clear the organism or harbor the organism and not show clinical signs for months to years? Reinfection in endemic areas is always possible, so it is difficult to distinguish from latency. The presence of coinfections with other tick-borne diseases such as A. platys or Bartonella spp. can make the clinical signs vary and difficult to attribute to a single specific agent; response to treatment may be less than expected than with just CME because of altered immune defenses.

Laboratory Findings

Clinicopathologic abnormalities most characteristic for CME are thrombocytopenia and mild regenerative anemia. However, infected dogs may have normal platelet counts. Dogs in the severe chronic phase of the disease, months to years after infection, may develop pancytopenia as a result of hypoplasia of all bone marrow precursor cells. Granular lymphocytosis, which may be confused with well-differentiated lymphocytic leukemia, has been reported. Hyperglobulinemia is reported in approximately one third of cases and is usually a polyclonal gammopathy, but monoclonal gammopathies have been reported in dogs and cats. Hypoalbuminemia and proteinuria have been found in all stages of the disease and may be asymptomatic. A common presentation of CME is the subclinical stage usually found incidentally with mild to moderate thrombocytopenia with the platelet count usually not below 60,000 (× 10³/µl), and the infected dog usually is not bleeding. Diagnosis of the disease at this stage and appropriate treatment are imperative so that the more severe, chronic phase does not occur. The chronic phase occurs when the bone marrow has been infected for weeks to months with irreversible bone marrow damage ensuing. The chronic stage often is not responsive to treatment and dogs either die or are euthanized because of poor quality of life.

Diagnostic Evaluation

Serologic test results can be of benefit in the diagnosis of CME in dogs. Serum antibodies can be detected by use of the indirect fluorescent antibody (IFA) assay; different point-of-care kits also are available commercially in some countries. In the IFA assay, it can take 7 to 28 days for a dog to become seropositive after initial infection. Clinical signs of CME may be present before the development of serum antibodies, and therefore the E. canis serum antibodies can be negative in acutely infected dogs. Repeat serologic testing in 2 to 3 weeks may show seroconversion and should be performed on dogs suspected of having CME. An E. canis IFA titer of more than 1 : 10 but less than 1 : 80 is considered suspect and should be repeated in 2 to 3 weeks. One point-of-care assay used to detect E. canis antibodies is calibrated to be positive at an IFA titer of approximately 1 : 100 or more (SNAP 4DX Plus). There is cross-reactivity between E. canis and other Ehrlichia spp. in some currently available antibody assays.

Positive E. canis antibody titers do not distinguish exposure from active infections. In endemic areas there are seropositive dogs exposed to the organism that either have cleared the organism naturally or may be infected currently. Serum antibody titers do not correlate with the duration of infection or the severity of disease. Apparently clinically ill or apparently healthy dogs with a positive antibody titer are not infected necessarily with E. canis and need further diagnostic investigation. Methods to document current infection include blood culture, cytologic demonstration of morulae, and amplification of E. canis DNA from blood or tissues by polymerase chain reaction (PCR). Blood culture for E. canis takes up to 8 weeks to become positive, is expensive and not widely available, and therefore is considered a research tool. Morulae are clusters of E. canis organisms found within mononuclear cells that stain purple on hematoxylin-eosin (H&E) blood smears. Detection of morulae confirms current infection; however, the sensitivity is low because morulae of CME are found rarely because they are present in the acute stage of the disease when most patients are infected subclinically. Because of these limitations, further evaluation of dogs for current CME infection generally is done by PCR assay, and positive test results confirm active infection. In general, E. canis DNA can be amplified from blood of experimentally infected dogs as soon as 4 to 10 days after the initial infection. PCR blood testing is specific for active infection and can detect infection earlier than IFA titers. However, healthy dogs also can be PCR positive, so this test also fails to prove definitely that the laboratory and clinical abnormities are related to CME. Not all commercial diagnostic laboratories are the same, and PCR assay results can be limited by quality controls used, which can result in false-positive and false-negative results.

The clinical diagnosis of CME usually is based on the combination of characteristic clinical signs, clinicopathologic abnormalities consistent with CME, a positive E. canis antibody titer, or a positive E. canis PCR assay on blood or tissue. Patients meeting these criteria should be treated for the infection. Whether to treat apparently healthy, seropositive dogs with no laboratory abnormalities is controversial. The pros and cons are discussed in the ACVIM Consensus Statement on Ehrlichial Disease of Small Animals from the Infectious Disease Study Group of the ACVIM (Neer et al, 2002). In one study using client-owned dogs, the authors concluded that serology alone should not be used to make a treatment decision (Hegarty et al, 2009).