Ehrlichiosis, Anaplasmosis, and Related Infections in Animals
Ehrlichiosis is an infection caused by obligate, intracellular bacteria that primarily affect cells of the immune system in dogs, cats, and people. In the past, the causative organisms 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, the term “ehrlichiosis” is still sometimes used to broadly describe these infections.
Canine monocytic ehrlichiosis is 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. The closely related pathogen E chaffeensis causes human monocytic ehrlichiosis 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 (a pathogen of rodents) 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, causes illness in dogs and horses. It also causes 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 distribution. Acute E canis cases in dogs 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 sylvatic 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. White-tailed deer are considered reservoir hosts for E chaffeensis and dogs are a probable 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 and Anaplasma spp. Signs arise from involvement of the hemic and lymphoreticular systems; many dogs experience self-limiting infection, but some may develop a secondary quiescent phase of disease followed by a severe and life-threatening third chronic stage.
Clinical findings in acute ehrlichiosis include:
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. 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. Vasculitis and immune-mediated mechanisms induce a thrombocytopenia and a risk of bleeding.
Clinical findings of chronic ehrlichiosis based on the predominant organs affected and may include:
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 milder and more self-limiting. Thrombocytopenia and mild leukopenia or leukocytosis may occur during the acute course of infection. 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 hematologic abnormalities are common findings with ehrlichiosis infections, a CBC is an important screening test. Infected animals often have thrombocytopenia. The 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. However, requesting a smear of concentrated buffy coat and examining the feathered edges of blood slides can improve sensitivity.
Serologic tests for ehrlichiosis are available based on enzyme immunoassays and immunofluorescent antibodies. The IgG antibody response to infection may be delayed for several weeks, and IgM titers can be low; thus, serology may be negative early in the course of the disease. Furthermore, antibodies can persist for months or years after infection, making serology problematic for diagnosis of clinically significant 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 four-fold 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. Serologic cross-reactivity is strong among E canis, E chaffeensis, and E ewingii, and among A phagocytophilum and A platys. 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.
Serologic testing may be done using in-house point-of-care tests and by sending blood to local diagnostic laboratories. Testing is often offered as part of "panels" for tickborne disease, and considerable care is required to interpret positive serology for one or more pathogens in light of compatible clinical illness.
PCR detects 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 although false-positive testing can occur briefly after treatment because the target for the test is DNA, which may remain at a site even after the pathogen has been killed. PCR is increasingly available through commercial veterinary laboratories as well as at veterinary schools and research institutions. PCR is also available through several commercial human laboratories.
Differential diagnoses for ehrlichiosis and anaplasmosis include:
To treat infection with Ehrlichia and Anaplasma spp, the drug of choice 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 week to develop in acute cases.
Recommended drug dosages for treatment of ehrlichiosis are:
Doxycycline: 5–10 mg/kg/day, PO or IV, for 10–21 days (drug of choice)
Tetracycline: 22 mg/kg, PO, three times a day (≥2 weeks, acute cases, 1–2 months, chronic cases)
Imidocarb diproprionate: 2 doses, 5–7 mg/kg, IM, 2 weeks apart (also effective for some strains of babesiosis)
In acute cases receiving appropriate antibiotic therapy, body temperature is expected to return to normal within 24–48 hours after treatment. In chronic cases associated with E canis infection, the hematologic abnormalities may persist for 3–6 months, although clinical response to treatment often occurs much sooner. If a dog is thought to have chronic ehrlichiosis, the E canis antibody titer and whole blood PCR should be repeated after 6 months of illness to confirm successful therapy. Serum titers that persist at lower but positive levels should be rechecked in another 6 months to ensure they are not increasing.
Supportive therapy may be necessary in animals with high fever or those with chronic disease complicated by wasting and specific organ dysfunction. NSAIDs and appropriate fluid therapy may help reduce fever. Animals with anemia or severe thrombocytopenia should be treated with platelet or whole-blood transfusions as appropriate, particularly if hemorrhage is extensive. Concurrent broad-spectrum antibiotics may be needed if a dog has severe leukopenia.
Prevention of ehrlichiosis and anaplasmosis is accomplished by controlling ticks on dogs. Dogs in areas infested by ticks should be limited from walking off-trail, in certain grassy areas, and where there may be ticks in some leaf litter. They should be examined after walks, with ticks removed carefully (to prevent human exposure), although it is unrealistic that owners will find all ticks in the coat of a dog. Multiple topical medications are available to prevent tick bites, and these should be used in compliance with labeling before bringing dogs into areas infested with ticks. 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.
Multiple ehrlichioses and anaplasmoses may be transmitted by ticks from wildlife to pets and people (or from dog to dog in the case of canine monocytic ehrlichiosis).
Ehrlichiosis and anaplasmosis have similar clinical manifestations, with acute fever and hematologic abnormalities.
Maintaining an index of suspicion for infection based on known tick activity, and using appropriate diagnostic testing, are important to make diagnoses of ehrlichiosis and anaplasmosis and to implement effective treatment.