Making Sense of Ehrlichiosis

Making Sense of Ehrlichiosis

Leah A. Cohn, DVM, PhD, DACVIM (SAIM) Professor, University of Missouri - College of Veterinary Medicine

Ehrlichia, members of the family Anaplasmataceae, are obligate intracellular gram-negative bacteria that are transmitted through feeding of vector ticks. The first recognized disease caused by Ehrlichia, identified in Algeria in the 1930’s, was caused by Ehrlichia canis. This potential pathogen is still an important cause of vector borne disease of dogs thoroughly the temperate regions of the world. Since the 1930’s many additional species of Ehrlichia have been recognized. These have different vectors, different cellular tropism, different reservoir and diseased hosts, and different pathogenicity and virulence. Diagnosis of disease and recognition of infection have similarities and differences. Besides supportive care and attention to complicating or co-morbid conditions, the treatment of all Ehrlichial infections usually relies on tetracycline antibiotics.

The three ehrlichial species of most importance for the small animal practitioner to understand are E. canis, E. ewingii, and E. chaffeensis (table 1). Other ehrlichial species occasionally recognized in diseased dogs, such as Panola Mountain Ehrlichia and E. muris eauclairensis will not be further considered here. Virulence of the considered infections depends not only on organism species and strain but also inoculum and host genetic background and immunologic status. Co-morbid infections also impact diagnosis, illness, and treatment.

E. canis

The original disease-causing species of Ehrlichia is still the most important as a canine pathogen. Transmitted by brown dog ticks in as little as 3 hours of feeding time, the disease is found in all the temperate regions of the world where the tick is found (essentially everywhere with warm weather other than New Zealand!). Different strains of E. canis may have difference in virulence. Pure bred dogs, especially German Shepherds, often seem to have a more severe clinical course. The disease course in the USA from E. canis seems to be less severe (and less often lethal) than caused by E. canis infections in much of the world.

There are three unique phases to the infection with E. canis. First is an acute infection that can be accompanied by vague febrile illness with or without ocular or neurological signs. In the USA especially, these signs may be quite mild and resolve without therapy. From there, the dog may enter a subclinical phase of infection where there are no discernable clinical signs of illness and all laboratory parameters are normal (resolution of thrombocytopenia typical of acute infection occurs in this phase). This subclinical phase may last for weeks, months, years, or for the life of the infected dog. Some portion of dogs with subclinical infection will go on to develop illness due to chronic canine monocytic ehrlichiosis (CME). The manifestation of illness is again quite variable. Among the more severe consequences are pancytopenia, hyperglobulinemia that can mimic multiple myeloma, bleeding diathesis, weight loss and/or muscle atrophy, uveitis or retinal hemorrhage, neurologic signs, and proteinuria with or without azotemia. Opportunistic infections may also occur.

E. ewingii

This pathogen causes granulocytic ehrlichiosis in dogs but is also an important zoonotic pathogen. Transmitted by the lone star tick, this infection is limited to areas in which that tick is endemic. The lone start tick is overwhelmingly the most common tick vector for disease in the state of Missouri. The reservoir for this pathogen seems to be canids, and infection in dogs is often subclinical. In fact, in one study as many as 23% of dogs from mid Missouri tests as a part of a prevalence study were seropositive for E. ewingii. While most infected dogs remain well, a proportion of infected dogs will develop acute clinical signs dominated by polyarthropathy, neurologic disease manifestations, and a febrile illness.

Infection with E. ewingii can be long lasting but the majority of disease manifestations seem to follow infection as an acute illness. There may be chronic infection consequences including renal disease with proteinuria +/- azotemia but this is less well characterized. Luckily, while morbidity of acute infection can be severe mortality is not reported. Disease resolves very quickly with treatment and the severe acute manifestations seem to resolve even without antimicrobial therapy.

E. chaffeensis

E. chaffeensis is predominantly a human pathogen. It is transmitted by the same lone start tick that transmits E. ewingii. This means that is shares geography with E. ewingii and is limited to the southeaster, southern midwestern, and mid Atlantic states. In the same prevalence study that found nearly a quarter of mid Missouri dogs had evidence of E. ewingii infection, 17% had evidence of E. chaffeensis infection. This pathogen has a mononuclear cell tropism like E. canis. It can cause very serious disease, up to and including death, in infected people. Experimental infection in dogs leads to thrombocytopenia but no clinical disease manifestations. Dogs with illness and natural infection have been reported.

Diagnosis

Screening of healthy dogs is a different subject than diagnosis of disease; screening will be addressed in a separate lecture. Routine laboratory tests can demonstrate suggestive findings such as thrombocytopenia (any species of Ehrlichia) or non-regenerative anemia and leukopenia (CME due to E. canis). Recognition of morulae in either mononuclear cells (E. canis) or granulocytes (E. ewingii) can establish a diagnosis but is very insensitive and is not even entirely specific. Morulae are most often visible in the acute disease state so recognition of morulae in dogs with CME is rare. The odds of finding morulae are increased by examination of a buffy coat, and morulae are sometimes found on joint fluid cytology or microscopic examination of cerebrospinal fluid. Granulocytic morulae are identical to the morulae of Anaplasma phagocytophilum but the two infections (which have similar clinical manifestations) can be distinguished by geography, serology, or molecular techniques. Other abnormalities on chemistry profile (eg, hypoalbuminemia, hyperglobulinemia, azotemia) or urinalysis (eg, proteinuria) are important but not routinely identified and not specific. Tests such as bone marrow cytology or serum protein electrophoresis may have utility in some scenarios more likely to occur with CME than with acute infection.

Serologic antibody testing is the most commonly used diagnostic technique, either using ELISA, IFA, or Western immunoblotting. Like all antibody-based serology, some time is required for seroconversion, meaning that acute infection can occur in seronegative dogs. Serology can be done as a Point-of-Care

test such as the extremely sensitive and specific IDEXX 4Dx Plus or as a send-off quantitative titer. Quantitative titers can be useful in looking for a 4-fold increase in titer compatible with acute infection. Titer in chronic infection is typically stable and sustained and often quite high; high titers can persist despite antimicrobial therapy suggesting that treatment may not entirely eliminate the pathogen. Serology can be more or less specific but there is considerable cross reactivity on the IDEXX 4Dx Plus test. This means that a dog with E. chaffeensis could test positive for Ehrlichia without identifying a specific species type. It is difficult to find a lab offering commercial serology to differentiate between Ehrlichia species causing exposure.

Polymerase chain reaction (PCR) testing can be used to detect these pathogens which can be found in blood cells. PCR testing is most likely to sensitive early in infection with waxing and waning numbers of pathogens in the blood during chronic infection. This means that a negative PCR test cannot rule out infection but a positive PCR confirms the presence of pathogen. Animals with positive PCR for Ehrlichia in tissues such as the spleen or bone marrow can be negative on peripheral blood.

Treatment

Treatment relies on the use of anti-rickettsial antimicrobial therapy and supportive care. In general, acute illness with any of the three species discussed here has an excellent prognosis with a rapid response to treatment with doxycycline or minocycline (10 mg/kg/day, either q 24 h or divided BID). A duration of 2 weeks is likely adequate to address acute illness such as that seen with E. ewingii infection but a more protracted 28-day treatment course is recommended for chronic infection.

Chronic infection can be difficult (or even impossible) to eliminate. Doxycycline and minocycline remain drugs of choice but rifampicin may have utility as well. There is no point in repeating serology after treatment as antibody response can persist, and there is limited utility to PCR because a negative blood PCR does not prove the pathogen has been eliminated. Instead, monitoring of therapy for CME should include monitoring of concurrent issues such as pancytopenia.

Supportive care is often required for dogs with CME. This may include blood transfusion, colony stimulation with drugs such as filgrastim, antibiotics for secondary infections, treatment of proteinuria and/or azotemia, and the like.

Prevention and Public Health

Although work on vaccination is ongoing, the best way to prevent infection is to prevent tick feeding. Stringent ectoparasite control is key and should be used year-round, especially as brown dog ticks prefer to live in buildings (floors, attics, walls) and may thus survive year-round. Repeat infections seem to be possible with any or all of the ehrlichial pathogens with no lasting immunity. A second infection could have different more severe consequences than the first.

Blood donor dogs should be screened for Ehrlichia and kept on stringent ectoparasite control programs.

While both E. ewingii and E. chaffeensis are zoonotic infections they cannot be transmitted directly from the dog to a person but require a tick vector. People removing ticks should use caution both to

avoid squeezing the tick and injecting additional pathogen in the pet but also to avoid exposing themselves. Caution is also suggested with collecting blood or tissues from infected dogs.

Table 1

Species Cellular tropism Vector tick Zoonotic potential

E. canis Mononuclear Rhipicephalus sanguineous (Brown dog tick) E. ewingii Granulocytic Amblyomma americanum (Lone star tick) E. chaffeensis Mononuclear Amblyomma americanum (Lone star tick) Canine pathogen (possible very rare human illness) Canine and human pathogen

Human pathogen (possible rare canine illness)

Suggested readings

Beall, MJ, et al. “An Improved Point-of-Care ELISA for the Diagnosis of Anaplasmosis and Ehrlichiosis During the Acute Phase of Tick-Borne Infections in Dogs” Topics in Companion Animal Medicine 51, 2022 https://doi.org/10.1016/j.tcam.2022.100735. Burton, Wade, et al. "Association between exposure to Ehrlichia spp. and risk of developing chronic kidney disease in dogs." Journal of the American Animal Hospital Association 56.3 (2020): 159164. Diniz P, et al “Ehrlichiosis and Anaplasmosis: An Update”. Veterinary Clinics of North America, 52(6):1225-1266, 2022. Mylonakis, ME., et al. "An update on the treatment of canine monocytic ehrlichiosis (Ehrlichia canis)." The veterinary journal 246 (2019): 45-53. Rodríguez-Alarcón, Carlos A., et al. "Demonstrating the presence of Ehrlichia canis DNA from different tissues of dogs with suspected subclinical ehrlichiosis." Parasites & Vectors 13.1 (2020): 1-7. Sato, Masahiko, et al. "Ehrlichia canis in dogs experimentally infected, treated, and then immune suppressed during the acute or subclinical phases." Journal of Veterinary Internal Medicine 34.3 (2020): 1214-1221.