Etiology, Epidemiology, and Transmission

Old World hepatozoonosis is a tickborne disease of wild and domestic carnivores caused by the protozoal agent Hepatozoon canis. It is unclear whether infections in wild and domestic Felidae are caused by H canis, or by another species of Hepatozoon. This organism is transmitted by the brown dog tick, Rhipicephalus sanguineus. In the late 1990s, unique features of the clinical presentation in North American dogs suggested that a different strain or species of Hepatozoon might be responsible for the disease in North America than in other parts of the world; in 1997, this suspicion was confirmed. The disease in North America is caused by H americanum, which is transmitted by the Gulf Coast tick, Amblyomma maculatum, rather than by the brown dog tick. Accordingly, the disease in North America is now recognized as a separate entity, American canine hepatozoonosis (ACH).

The mode of transmission of hepatozoonosis is not typical in the classical sense of a tickborne disease; like other species in the genus, H canis and H americanum infections occur when an infected tick, the definitive host, is ingested by the dog (or other vertebrate intermediate host). Sporozoites released from the mature oocysts in the tick's hemocoel enter the vertebrate host via the gut. Dogs can also acquire ACH by eating paratenic (transport) hosts that contain cystozoites, a resting stage of H americanum encysted in their tissues. Experimentally, cystozoite-engendered infection results in the same disease manifestations seen in dogs that ingest sporulated oocysts. It is unknown at present whether a similar path of infection may occur in H canis infections.

In much of the world (India, Africa, southeast Asia, the Middle East, southern Europe, and islands in the Pacific and Indian Oceans), dogs with hepatozoonosis usually have subclinical infections or only mild clinical signs. In these areas, immunosuppression caused by concurrent disease or other factors appears to play an important role in the manifestation of significant clinical signs. In the USA, immunosuppression or concurrent disease does not appear necessary to induce the more severe clinical signs typically seen with ACH.

ACH is an emerging disease that has primarily spread north and east from the Gulf Coast of Texas, where it was originally detected in 1978. The distribution of this parasite parallels the distribution of the Gulf Coast tick. Most cases in the USA have been diagnosed in Texas (primarily along the Gulf Coast), Oklahoma, and Louisiana; numerous cases have been reported from Alabama, and cases have been seen as far east as Tennessee, Georgia, and Florida. Sporadic cases have been reported from such disparate geographic locations as California, Washington, and Vermont; it is assumed that these dogs were relocated from endemic areas, because the Gulf Coast tick has not become established in such distant locations. H americanum may be found in Central and South America, as is A maculatum. Amblyomma ovale has been identified as a vector for H canis in South America. Molecular genetic evidence is emerging that suggests H canis infections may be more common in North America than previously thought, but ACH remains the more severe and more common form of hepatozoonosis in the New World.

Experimentally, dogs >4–6 mo old are resistant to infection with H canis. However, H americanum causes severe clinical signs, even in adult dogs. Because disease caused by H americanum is much more clinically significant than that caused by H canis, the descriptions in the remainder of this chapter refer primarily to ACH.

Clinical Findings

The tissue phases of the hepatozoonosis organism, especially those of H americanum, induce pyogranulomatous inflammation, which results in clinical signs. These signs, which may be intermittent, include fever, depression, weight loss, poor body condition, muscle atrophy, soreness, stiffness, and weakness; mucopurulent ocular discharge is common, and bloody diarrhea occurs occasionally. Surprisingly, many dogs maintain a normal appetite if food is placed directly in front of them, but they often will not move to eat, apparently owing to intense pain. Severe hyperesthesia or pain over the paraspinal region is a common finding on physical examination; cervical, joint, or generalized pain is also seen. Hyperesthesia manifests as stiffness and reluctance to move, as well as cervical and/or truncal rigidity. Fever, which may fluctuate with the waxing and waning of clinical signs, ranges from 102.7–106.0°F (39.3–41.0°C) and is unresponsive to antibiotics. Longterm sequelae include glomerulonephritis and amyloidosis.

Diagnosis

The most consistent laboratory abnormality is a neutrophilic leukocytosis, with counts ranging from 20,000–200,000 cells/μL. This is typically a pronounced, mature neutrophilia, although a left shift may be present. A mild to moderate normocytic, normochromic, nonregenerative anemia is also commonly found. The platelet count is typically normal to elevated. Mildly increased alkaline phosphatase, hypoalbuminemia, and increased CK may also be seen. Although profound hypoglycemia has been reported, this finding is thought to be an in vitro sampling artifact that results from increased metabolism of glucose by the overly abundant leukocytes. On radiographs, periosteal reactions may be seen involving any bone (including the skull and vertebrae). These periosteal reactions resemble those of hypertrophic osteoarthropathy, except that lesions tend to be proximal rather than distal with ACH, often markedly obvious in long bones. The physiologic basis of the bone lesions has not been determined.

Definitive diagnosis of hepatozoonosis is made by finding gamonts in peripheral blood leukocytes (using Romanowsky-type stains); identifying the typical cysts, meronts, or pyogranulomas in muscle biopsies; or detecting serum antibodies against H americanum sporozoites. In some dogs, multiple or sequential muscle biopsies may be necessary to detect the organism. Although an experimental serologic method of diagnosis (an ELISA that detects antibodies to H americanum sporozoites) has been developed, it is not available for routine diagnosis. Auburn University and North Carolina State University offer diagnostic tests for hepatozoonosis based on PCR. These tests have led to the realization that classical hepatozoonosis caused by H canis is more common in North America than previously known. Moreover, recognized variation in an 18S rDNA sequence from infected dogs has raised new questions about canine hepatozoonosis. It may be that still more species (or strains) that vary in pathogenecity and/or life cycle patterns will be found to cause disease in dogs.

Treatment

Hepatozoonosis is a lifelong infection in dogs. No known therapeutic regimen completely clears the body of the organism. In the past, treatment has been frustrating because most dogs showed only temporary improvement, with frequent relapses within 3–6 mo and death within 2 yr of diagnosis. Today, remission of clinical signs can usually be achieved through combination therapy, referred to as TCP, which consists of trimethoprim-sulfadiazine (15 mg/kg, PO, bid), clindamycin (10 mg/kg, PO, tid), and pyrimethamine (0.25 mg/kg, PO, sid); these drugs should be administered for 14 days. Unfortunately, remission with this therapy has often been short-lived, and dogs frequently relapse within 2–6 mo. However, an adjunctive treatment using decoquinate (a large animal anticoccidial drug) has been useful. Decoquinate does not resolve active clinical disease but may prevent clinical relapses; it is given after resolution of clinical signs as an adjunct to TCP therapy. The recommended dose for decoquinate is 10–20 mg/kg, PO, bid continuously for 2 yr. The advent of TCP combination therapy followed by daily decoquinate therapy has resulted in a marked improvement in the prognosis for dogs with hepatozoonosis.

Other, older treatments include imido-carb dipropionate (5 mg/kg, SC, given once), a combination of imidocarb dipropionate (6 mg/kg, SC, every 14 days) with tetracycline (22 mg/kg, PO, tid for 14 days), or the coccidiostat toltrazuril (5–10 mg/kg, SC or PO, sid for 3–5 days or 5 mg/kg, PO, bid for 4 days). The effect of imidocarb therapy has been inconsistent and may depend on the severity of signs and geographic location, both of which may be related to strain of organism causing disease. Similarly, although excellent initial clinical response to toltrazuril has been reported, relapses occurred, and there was no evidence that the cyst forms clear from the muscle tissue.

NSAID may be the best treatment for control of fever and pain, especially during the first few days of TCP therapy. Glucocorticoid administration should be avoided, because although steroids may provide temporary relief, longterm use can exacerbate the disease.

Prevention of access to ticks and discouraging predation are the most effective forms of control for hepatozoonosis. Predation presents a dual risk for acquiring ACH: prey captured/ingested by dogs could have infected ticks on their coats that would provide a source of sporozoites; additionally, the prey could contain cystozoites (at least in the case of H americanum) that are also infectious.

There is no known zoonotic risk with hepatozoonosis.

Last full review/revision July 2011 by S. A. Ewing