Ehrlichia Infections in Dogs

EHRLICHIOSIS : EVOLVING IMPLICATIONS FOR VETERINARY MEDICINE Edward Edward B. Breitschwerdt, DVM, Diplomate, ACVIM
Professor Veterinary Medicine
North Carolina State Veterinary School
http://www.cvm.ncsu.edu/

Objectives

1.Describe the clinicopathologic abnormalities associated with Ehrlichia canis, Ehrlichia chaffeensis, and Ehrlichia equi infection in dogs.

2.Discuss factors which differentiate ehrlichiosis from Rocky Mountain spotted fever in dogs. Describe how you would confirm a diagnosis of ehrlichiosis.

3.Describe therapeutic and management recommendations for a hunting-dog kennel, endemically infected with Ehrlichia canis.

Rickettsial organisms in general, and Ehrlichia species in particular, are difficult to isolate from animals or human patients using conventional tissue culture systems.

1 Therefore, substantiation of a clinical diagnosis of ehrlichial infection has been limited to visualization of intracellular rickettsiae (individual organisms or morulae) on stained blood smears, or to the use of serologic testing for E. canis antibodies. Obviously, both of these modalities can have substantial limitations for the diagnosis of a chronic infectious disease. Until the recent identification of monocytic2 and neutrophilic3,4 human ehrlichiosis in Japan, Sweden and the United States, Ehrlichia species were considered solely animal pathogens, for which limited interest or funding were available for research studies. These and other historical factors resulted in substantial limitations in our understanding of infections caused by members of the genus Ehrlichia. In dogs, ehrlichial infection is caused by Ehrlichia canis, Ehrlichia ewingii, Ehrlichia equi, Ehrlichia platys, and an as yet uncharacterized Ehrlichia species, genetically similar to Ehrlichia risticii.

Based on current understanding, E. canis is the most important cause of ehrlichial infection in dogs worldwide. However, future studies may confirm that granulocytic ehrlichiosis, caused by members of the E. phagocytophillia genogroup (E. equi, E. phagocytophillia, (HGE) Human Granulocytic Ehrlichiae) are capable of infecting cats, dogs, horses, cattle and humans in endemic regions of the Northern Hemisphere. When we review the spectrum of disease manifestations attributed to E. canis infection, there is considerable variation in the type, duration, and severity of historical, physical, and clinicopathologic abnormalities reported in naturally-infected dogs. Whether the substantial variation in disease manifestations or clinicopathologic abnormalities reflect strain differences in pathogenicity, variability in the immunologic response of the host to the rickettsia, co-infection with other tick- transmitted pathogens, or other unknown factors remains unclear. Recent evidence suggests that each of these factors may play a role in selected E. canis cases.

The "typical" acute clinical presentation of E. canis infection is associated with nonspecific findings, including loss of appetite, fever and enlarged lymph nodes. Chronically-infected dogs may appear healthy or may develop chronic weight loss, peripheral edema, or bleeding abnormalities, including prolonged bleeding from venipuncture sites, bruising, ocular hemorrhage or nose bleeds. Factors responsible for the induction of disease signs in chronically- infected dogs remain uncharacterized. Since both experimentally and naturally-infected dogs can remain healthy for several years following exposure, documentation of seroreactivity to E. canis antigen in a sick dog does not confirm that the dog's illness is related to E. canis infection. For example, an older dog residing in an E. canis endemic region might present with fever, enlarged lymph node, bruising, and abnormal protein levels. Despite chronic infection and positive blood test to E. canis antigen, all of the dog's disease manifestations could be attributed to lymphosarcoma, or other neoplastic or infectious diseases. In this instance, lack of response to anti-rickettsial drugs would be expected due to concurrent neoplastic disease. An additional important problem confronting clinicians relates to valid documentation of therapeutic elimination of E. canis infection. There is scanty information in the veterinary literature regarding long-term post-treatment follow-up of dogs with ehrlichiosis. More recent studies, including those from our laboratory, indicate that many naturally and experimentally-infected dogs clear E. canis infection following 2 weeks of doxycycline (5 mg/kg every 12 hours) therapy. Despite rapid clinical improvement, some dogs remain hematologically abnormal for several months following a 2 week course of doxycycline. It remains unclear as to whether persistence of high post-treatment antibody titers and/or the persistence of PCR amplicons in some dogs correlates with persistence of ehrlichial infection. A recent experimental study documented treatment failure in 3 of 5 dogs treated with 10 mg/kg of doxycycline for 7 days,5 whereas 8/8 dogs treated with 5 mg/kg every 12 hours for 14 days cleared the infection. Generally, a duration of therapy longer than 7 days is recommended; therefore, the relevance of this experimental observation to treatment outcome in natural infection awaits additional study. We have also isolated other potential pathogens, particularly Bartonella vinsonii, from "refractory" cases, which may have contributed to the persistence of disease manifestations.

In 1994, Kakoma and colleagues reported serologic evidence of over 100 cases of atypical canine ehrlichiosis with 3 fatalities.7 These dogs were not positive to E. canis antigen by immunofluorescence antibody (IFA), but were reactive to E. risticii antigen at generally low antibody titers. Ehrlichia risticii is the cause of Potomac horse fever. Serum samples were derived from California, Texas, Arizona, Illinois, Washington, Florida, and Michigan. Isolates obtained from 3 dogs were morphologically and genetically (based on partial 16S rRNA gene sequence) indistinguishable from E. risticii. Previous experimental infection of dogs and cats with E. risticii failed to induce clinical abnormalities, and successful experimental transmission of a dog isolate has not been reported. Clinical abnormalities were described for 6 dogs with atypical ehrlichiosis and include: lethargy, vague signs of abdominal discomfort with intermittent vomiting, persistent bleeding or bruising, generalized joint, limb swelling , and posterior paralysis. Hematologic abnormalities were variably present and included: anemia, low platelet, prolonged bleeding time, and elevated calcium levels. Therapy with tetracycline also appears to be variably efficacious for treatment of this organism, with substantial improvement in some dogs and a complete lack of response in other dogs. The author's propose that pending additional research, the canine isolate be referred to as E. risticii subsp. atypicalis. The definitive pathophysiologic characterization of this rickettsiae as a cause of disease in dogs awaits additional study.

Recently, human infection has been associated with a granulocytic Ehrlichia species in the United States. There have been several human fatalities, particularly in the elderly. Experimentally, isolates obtained from human patients will infect dogs, cats, sheep and horses that appear to be naturally infected in regions where human disease has been reported. Genetically, analysis of eubacterial 16S ribosomal DNA derived from human isolates is indistinguishable form Ehrlichia equi or Ehrlichia phagocytophilia. In 1982, Madwell and Gribble transmitted granulocytic ehrlichiae morulae via blood transfusion from a naturally- infected dog to 2 horses, and from these horses to both dogs and cats. Granulocytic human ehrlichiosis has been reported in Minnesota, Wisconsin and Massachusetts, but most probably has a much broader distribution within the United States. Experimentally, Ixodes scapularis ticks are competent vectors for transmission of granulocytic ehrlichiae, and a 10% prevalence of infection occurs in adult I. scapularis from Wisconsin and Nantucket, Massachusetts. Tick transmission to a broad host range, including cats, dogs, horses, sheep, goats, rodents, nonhuman primates and humans is probable. In naturally-infected dogs, fever, lethargy, thrombocytopenia, elevated serum alkaline phosphatase and amylase activities, and hypoalbuminemia are the more frequently identified abnormalities.7 Diagnosis requires visualization of granulocytic morulae or seroreactivity to E. equi antigen. Treatment with tetracycline elicits a rapid clinical response. Current data indicates that this granulocytic rickettsia is the cause of an important emerging zoonotic disease.

Several recent reports emphasize the potential for simultaneous infection with multiple tick- transmitted pathogens. For example, I. scapularis ticks can induce human infection with B. burgdorferi, E. equi (HGE) and Babesia microti. In dogs, we have observed simultaneous infection with E. canis or E. chaffeensis, Bartonella vinsonii, Babesia canis, and Rickettsia rickettsii. Infection with both E. ewingii and E. canis has been reported in naturally-infected dogs from Oklahoma. When considered in conjunction with the isolation of an organism genetically identical to E. canis from a veterinarian from Venezuela, the recent documentation of E. chaffeensis infection in dogs and E. phagocytophilia infection in multiple animal species, the species specificity of Ehrlichia species should perhaps be re-examined.

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