Etiology and life cycle
Canine hepatozoonosis is a tick-borne disease caused by apicomplexan protozoa. Two different species of Hepatozoon infect dogs, H. canis in the Old World and South America, and H. americanum in the southern USA. H. canis infection (HCI) varies between being asymptomatic in dogs with a low parasitemia, to a severe disease with anemia, profound lethargy and cachexia in dogs with a large number of circulating parasites. H. americanum infection (HAI) is manifested mainly by gait abnormalities and musculoskeletal pain due to myositis and periosteal bone lesions. HAI is an emerging disease that is spreading north and east from Texas where it was originally detected in 1978. It has since been reported also from Louisiana, Alabama, Oklahoma, Georgia, Tennessee, and Florida.
In contrast to many tick-borne pathogens that are transmitted via the tick salivary glands, Hepatozoon transmission to the dog takes place by ingestion of a tick or parts of ticks containing Hepatozoon oocysts. Sporozoites release from the oocysts in the dog's intestine and penetrate the gut wall. The sporozoites invade mononuclear cells and disseminate hematogenously or via the lymph to target organs. Merogony occurs in the dog's parenchymal tissues and is followed by gametogony in leukocytes. The tick, which serves as the definitive host, becomes infected when feeding on a parasitemic dog. Hepatozoon gamonts release from the dog leukocytes within the tick gut and gametogenesis takes place followed by fertilization and sporogony with the formation of oocysts in the tick's hemocoel.
The main vector of H. canis is the brown dog tick Rhipicephalus sanguinis. R. sanguineus is found in warm and temperate regions all over the world, making the potential distribution of H. canis wide. The Gulf Coast tick Amblyomma maculatum is the vector of H. americanum. A. maculatum's distribution appears to be restricted to some parts of America. Both of the Hepatozoon species that infect dogs are transmitted transstadially from the nymph to the adult stage, in their tick vectors.
Hepatozoon canis mainly infects the hemolymphatic tissues and blood-forming organs including the bone marrow, lymph nodes and spleen. H. americanum primarily infects skeletal and cardiac muscular tissues and causes myositis and severe lameness. H. canis appears to be well adapted to its canine host, and is often detected in necropsy or on a peripheral blood smear as an incidental finding. H. americanum induces a violent course of disease in experimentally and naturally occurring infection. It may have recently crossed the species barrier from the coyote or another wild mammalian host to the domestic dog.
Clinical and laboratory findings
HCI varies from being asymptomatic in apparently healthy dogs to a severe and life-threatening disease in animals with extreme lethargy, cachexia and anemia. An asymptomatic to mild disease is the most common presentation of the infection and it is usually associated with a low level of H. canis parasitemia (1-5 %), while a severe illness is found in dogs with a high parasitemia often approaching 100% of the peripheral blood neutrophils. High parasitemia rates are sometimes accompanied by extreme neutrophilia reaching as high as 150,000 leukocytes/μl blood. A seroepidemiological study of HCI in Israel revealed that 33% of the dogs surveyed had been exposed to the parasite as indicated by the presence of anti-H. canis antibodies. Only 3% of the seropositive dogs had detectable blood gamonts and only 1% had severe clinical signs associated with the infection. A case-control study of dogs admitted to a veterinary hospital in Israel with H. canis parasitemia indicated that 15% had a high number of circulating parasites (> 800 gamonts/μl) accompanied by elevated body temperature, lethargy, weight loss, anemia and hyperglobulinemia. Post-mortem findings from some of the dogs with a high parasitemia revealed hepatitis, pneumonia and glomerulonephritis associated with H. canis meronts. Meronts of H. canis were also found in the spleen, bone marrow and lymph nodes.
Concurrent HCI and infection with other canine pathogens is common. Co-infections with H. canis reported include: parvovirus, Ehrlichia canis, Toxoplasma gondii and Leishmania infantum. Immune suppression induced by an infectious agent, an immature immune system in young animals or immunodeficient conditions, influence the pathogenesis of new H. canis infections or the reactivation of pre-existing ones. Treatment with an immunosuppressive dose of prednisolone was followed by the appearance of H. canis parasitemia in dogs with experimental HC.
In contrast to the generally mild disease found in HCI, HAI is almost always a severe disease that leads to debilitation and death. Most dogs diagnosed with HAI are presented with fever, gait abnormalities, muscular pain induced by myositis, generalized muscular atrophy and mucopurulent ocular discharge. The pain can be generalized or localized in the lumbar and cervical spine, or joints. Gait abnormalities include stiffness, hind limb paresis, ataxia and inability to rise. A marked neutrophilia is one of the consistent hematologic findings in HAI. Leukocyte counts range from 30,000 to 200,000/ml blood. Serum biochemical abnormalities include increased alkaline phosphatase activity and hypoalbuminemia.
HCI is usually diagnosed by microscopic detection of intracellular H. canis gamonts in stained blood smears. The gamonts are found in the cytoplasm of neutrophils or monocytes, have an ellipsoidal shape and are about 11 by 4 micrometers. H. canis meronts found in infected tissues contain elongated micromerozoites arranged in a circle around a clear central core. This form is often referred to as a "wheel spoke" meront. Meronts containing macromerozoites and small monozoic tissue cysts have also bee described in HCI.
H. americanum parasitemia is rare and usually does not exceed 0.1% of the leukocytes. Confirmation of HAI is commonly carried out by muscle biopsy and demonstration of parasites in cysts or granulomas. Histopathology of skeletal muscles from dogs with HAI reveals pyogranulomatous myositis and large round to oval cysts (250-500 micrometer diameter) containing a central nucleus surrounded by concentric rings of membranes. These cysts are sometimes referred to as having an "onion peel" appearance due to the structure of the membranes surrounding a core mass. Radiography of the long bones or pelvis demonstrating periosteal proliferation can be used for screening suspected animals.
An indirect fluorescent antibody test (IFAT) for anti-H. canisantibodies was used for epidemiological studies in Israel and Japan. Sera from dogs with HAI showed only a low degree of cross reactivity to H. canis antigens. Antibodies to H. canis of the IgM and IgG classes were detected in experimentally infected dogs 16 and 22 days post-infection, respectively, which was before the detection of gamonts in the blood at 28 days postinfection. It was suggested that antibodies reactive with gamonts antigen may be formed against conserved antigens found in earlier life stages of H. canis. An ELISA for H. canis antibodies has also been developed recently and used for studies in Israel and Greece.
A serological test for HAI using sporozoite antigen derived from ticks has been developed for the detection of ani-H. americanum antibodies. This assay was found to be as sensitive as the muscle biopsy for the diagnosis of HAI.
HCI is treated with imidocarb dipropionate at 5-6 mg/kg every 14 days until gamonts are no longer present in blood smears. Oral doxycycline at 10 mg/kg/day for 21 days is also used in combination with imidocarb dipropionate for treatment of HCI. Elimination of H. canis gamonts from the peripheral blood may require 8 weeks. HAI is treated with a combination oral therapy of trimethoprim/sulfa (15 mg/kg every 12 hours), pyrimethamine (0.25 mg/kg every 24 hours), and clindamycin (10 mg/kg every 8 hours). After remission from clinical signs is attained, it can be prolonged with the oral administration of the coccidiostat decoquinate at 10-20 mg/kg mixed in the food every 12 hours. Relapse of clinical signs is common following the discontinuation of treatment. Supportive therapy with non-steroidal anti-inflammatory drugs is effective in relieving pain and fever in dogs with HAI. Prevention of exposure of dogs to ticks by the use of acaricides is warranted to control the spread of both forms of canine hepatozoonosis.
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