Ehrlichiosis and Related Infections
In the past, a number of obligate intracellular organisms that infect eukaryotic cells were classified in the genus Ehrlichia on morphologic and ecologic grounds. With newer genetic analyses, these agents have been reclassified into the genera of Ehrlichia, Anaplasma, and Neorickettsia, all of which are in the family Anaplasmataceae. However, usage of the term “ehrlichiosis” to broadly describe these infections may still persist.
Canine ehrlichiosis is primarily caused by Ehrlichia canis, which predominantly involves monocytes; although it is not considered a primary zoonosis, human infection with this agent has been occasionally reported. Another common ehrlichial pathogen of dogs is E chaffeensis, which causes a monocytic form of illness and is the primary species causing human ehrlichiosis infection in the USA. Human cases are reported throughout the mid to southeastern and central USA. Several published reports of monocytic ehrlichiosis in cats suggest that feline infection may occur, albeit uncommonly. E ewingii, which primarily infects the granulocytes of susceptible hosts, has been isolated from dogs and people in the southern, western, and midwestern USA. In 2009, an organism either identical or related to E muris was identified as a cause of human illness in the upper Midwest; the role of this E muris–like (EML) agent as a possible pathogen of dogs or cats is currently unknown.
A phagocytophilum, formerly known as both E equi and the agent of human granulocytic ehrlichiosis, has been reported as a cause of illness in dogs. It is known to cause human illness in the USA, primarily in northeastern, upper midwestern, and western states. Infection with this agent is most appropriately referred to as anaplasmosis, and the pathogen is found predominantly in granulocytes.
A platys, which infects platelets, is the cause of infectious cyclic thrombocytopenia of dogs.
E canis is transmitted by the brown dog tick, Rhipicephalus sanguineus, which is found worldwide; accordingly, canine monocytic ehrlichiosis also has a worldwide enzootic distribution. Acute E canis cases may resemble infection with Rickettsia rickettsii (the agent of Rocky Mountain spotted fever, which can also be transmitted by the brown dog tick). Rhipicephalus ticks become infected with E canis after feeding on infected dogs, and ticks transmit infection to other dogs during blood meals taken in successive life stages. Blood transfusions, or other means by which infected WBCs can be transferred, may also transmit the pathogen. E chaffeensis and E ewingii have sylvan cycles in the environment that involve tick species and wildlife reservoir hosts. In the USA, E chaffeensis and E ewingii are transmitted by Amblyomma americanum, the lone star tick, and white-tailed deer are thought to play an important role as reservoir hosts. Dogs are also considered a possible reservoir for E ewingii. A case of human E ewingii contracted via blood infusion has been reported, and organ transplantation of E chaffeensis infection has been suspected. The ecologic cycle for the EML agent has not yet been elucidated but is suspected to involve Ixodes scapularis, the black-legged tick.
A phagocytophilum is transmitted by Ixodes species of ticks; in the northeastern USA, infection is transmitted by I scapularis, whereas infection in western states is primarily associated with I pacificus, the Western black-legged tick. In nature, the enzootic cycle is most likely associated with small rodents. People and domestic animals are incidental hosts of these pathogens. Human-to-human transmission via transfusion of packed RBCs has been reported; the risk of canine-associated infections after blood transfusion is unknown.
A platys is transmitted by R sanguineus and is enzootic in many parts of the USA and worldwide. Coinfection with E canis may occur, because the same tick vector is responsible for transmission of both pathogens.
In dogs, E canis causes the most potentially severe clinical presentation of the Ehrlichia spp. Signs arise from involvement of the hemic and lymphoreticular systems and commonly progress from acute to chronic, depending on the strain of organism and immune status of the host. In acute cases, there is reticuloendothelial hyperplasia, fever, generalized lymphadenopathy, splenomegaly, and thrombocytopenia. Variable signs of anorexia, depression, loss of stamina, stiffness and reluctance to walk, edema of the limbs or scrotum, and coughing or dyspnea may be seen. Most acute cases are seen in the warmer months, coincident with the greatest activity of the tick vector. Chronic cases may present at any time of year.
During the acute phase of E canis infection in dogs, the hemogram is usually normal but may reflect a mild normocytic, normochromic anemia; leukopenia; or mild leukocytosis. Thrombocytopenia is common, but petechiae may not be evident, and platelet decreases may be mild in some animals. Vasculitis and immune-mediated mechanisms induce a thrombocytopenia and hemorrhagic tendencies. Lymph node aspiration reveals hyperplasia. Death is rare during this phase; spontaneous recovery may occur, the dog may remain asymptomatic, or chronic disease may ensue.
Chronic ehrlichiosis caused by E canis may develop in any breed, but certain breeds, eg, German Shepherds, may be predisposed. Seasonality is not a specific hallmark of chronic infection, because appearance of chronic signs may be variably delayed after acute infection. In chronic cases, the bone marrow becomes hypoplastic, and lymphocytes and plasmacytes infiltrate various organs. Clinical findings vary based on the predominant organs affected and may include marked splenomegaly, glomerulonephritis, renal failure, interstitial pneumonitis, anterior uveitis, and meningitis with associated cerebellar ataxia, depression, paresis, and hyperesthesia. Severe weight loss is a prominent finding.
The hemogram is usually markedly abnormal in chronic cases. Severe thrombocytopenia may cause epistaxis, hematuria, melena, and petechiae and ecchymoses of the skin. Variably severe pancytopenia (mature leukopenia, nonregenerative anemia, thrombocytopenia, or any combination thereof) may be seen. Aspiration cytology reveals reactive lymph nodes and, usually, marked plasmacytosis. Frequently, polyclonal, or occasionally monoclonal, hypergammaglobulinemia develops.
Other ehrlichial infections caused by E chaffeensis, E ewingii, or A phagocytophilum appear clinically similar to acute E canis infection, but the clinical course is usually more self-limiting. Shifting leg lameness and fever of unknown origin may be present. Thrombocytopenia and mild leukopenia or leukocytosis may occur during the acute course of infection, which is clinically more discrete. Chronic canine disease, as seen with E canis infection, is not typically seen with other infections.
Dogs infected with A platys generally show minimal to no signs of infection despite the presence of the organism in platelets. The primary finding is cyclic thrombocytopenia, recurring at 10-day intervals. Generally, the cyclic nature diminishes, and the thrombocytopenia becomes mild and slowly resolves.
During the acute or self-limiting phase of E canis infections, lesions generally are nonspecific, but splenomegaly is common. Histologically, there is lymphoreticular hyperplasia and lymphocytic and plasmacytic perivascular cuffing. In chronic cases, these lesions may be accompanied by widespread hemorrhage and increased mononuclear cell infiltration in perivascular regions of many organs.
Because thrombocytopenia is a relatively consistent finding with these infections, a platelet count is an important screening test. Clinical diagnosis may be confirmed by demonstrating the organisms within WBCs or platelets, seen in intracytoplasmic inclusion bodies called morulae. This method of diagnosis lacks sensitivity, because low numbers of organisms make demonstration difficult. More commonly, a diagnosis is made by a combination of clinical signs, positive serum indirect fluorescent antibody (IFA) titer, and response to treatment. In-house tests for E canis, A phagocytophilum, A platys, and E ewingii based on enzyme immunoassay methods are also available. The antibody response may be delayed for several weeks; thus, serologic testing may not be a reliable diagnostic tool early in the course of the disease. Furthermore, antibodies can persist for months or years after infection, making in-house tests for the organisms problematic for confirmation of acute infection, particularly in highly enzootic areas where many dogs may have antibodies to these agents because of previous infections. Testing of paired sera and demonstration of increased antibody titers is recommended to confirm infection when possible, although treatment of suspected cases should never be delayed or withheld on the basis of test results, either positive or negative. Serologic cross-reactivity is strong between E canis, E chaffeensis, and E ewingii; some cross-reactivity to A phagocytophilum is also seen. In people, the EML agent shows cross-reactivity to E chaffeensis. In some areas, ~50% of dogs infected with E canis also have a titer to A platys, which likely reflects coinfection; cross-reactivity between these agents is not seen.
PCR has been used to detect and identify specific Ehrlichia and Anaplasma species in infected people and animals. Samples appropriate for PCR include blood, tissue aspirates, or biopsy specimens of reticuloendothelial organs, such as lymph nodes, spleen, liver, or bone marrow. PCR can also be used to detect the effectiveness of treatment in clearing infection. PCR is not routinely available through commercial veterinary laboratories, although some veterinary schools and research institutions offer it. PCR is available through several commercial human laboratories.
During the acute stage, differential diagnoses include other causes of fever and lymphadenomegaly (eg, Rocky Mountain spotted fever, brucellosis, blastomycosis, endocarditis), immune-mediated diseases (eg, systemic lupus erythematosus), and lymphosarcoma. During the chronic stage of E canis infection, differential diagnoses include estrogen toxicity, myelophthisis, immune-mediated pancytopenia, and other multisystemic diseases associated with specific organ dysfunction (eg, glomerulonephritis).
The drug of choice for infection with Ehrlichia and Anaplasma spp is doxycycline because of its superior intracellular penetration and bacteriostatic properties against rickettsiae. Doxycycline is recommended for dogs of all ages. If infection is suspected, dogs should be treated empirically; treatment should not be withheld or delayed pending laboratory results. Early seronegative tests should not be considered a reason to stop therapy, because antibodies may take ≥1 wk to develop in acute cases. The recommended dosage of doxycycline in dogs is 5–10 mg/kg/day, PO or IV, for 10–21 days. Tetracycline (22 mg/kg, PO, tid) can also be used for ≥2 wk in acute cases and 1–2 mo in chronic cases. Two doses of imidocarb dipropionate (5–7 mg/kg, IM), 2 wk apart, are variably effective against both ehrlichiosis and some strains of babesiosis. In acute cases receiving appropriate antibiotic therapy, body temperature is expected to return to normal within 24–48 hr after treatment. In chronic cases associated with E canis infection, the hematologic abnormalities may persist for 3–6 mo, although clinical response to treatment often occurs much sooner. Supportive therapy may be necessary to combat wasting and specific organ dysfunction; platelet or whole-blood transfusions may be required if hemorrhage is extensive. Concurrent broad-spectrum antibiotics may be needed if the dog has severe leukopenia. The E canis antibody titer should be measured again within 6 mo of illness to confirm a low or seronegative status indicative of successful therapy. Serum titers that persist at lower but positive levels should be rechecked in another 6 mo to ensure that they are not increasing.
Prevention is enhanced by controlling ticks on dogs, through use of reliable methods. In particular, medications and products with proven efficacy against R sanguineus are important to use. Because R sanguineus infestations can be problematic in kennels and around homes, and longterm tick control is needed for management, use of effective long-acting collars on all susceptible dogs might be considered; collars containing propoxur, amitraz, or flumethrin have proven activity against R sanguineus. Prevention of transfusion-associated transmission can be reduced by using seronegative screened blood donors, although new donors with a negative screen cannot be presumed free of infection for several weeks because they may be incubating infection. Prophylactic administration of tetracycline at a lower dosage (6.6 mg/kg/day, PO) is effective in preventing E canis infection in kennels where disease is endemic. Treatment must be extended for many months through at least one tick season if the endemic cycle is to be successfully eliminated, and tick control should be implemented as well.
E chaffeensis, E ewingii, and A phagocytophilum are considered zoonoses. Despite the occurrence of disease in both animals and people, the involvement of a required intermediate tick vector for transmission means dogs and other infected animals do not pose a direct transmission risk in normal circumstances. Infection in dogs may indicate a heightened risk of human infections related to tick exposure in a given area.