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 based on parasite morphology, tissue tropism, and pathogenesis. 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). Genetic and antigenic differences now documented between the North American and Old World organisms further support their classification as distinct species.
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, although monozoic cyst stages have been reported in the spleen of both experimentally and naturally infected dogs. It is possible that canids may serve as both transport and definitive hosts of H canis.
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 these dogs were relocated from enzootic areas, because the Gulf Coast tick has not become established in such distant locations. H americanum may be present in Central and South America, as is A maculatum, but to date, no autochthonous transmission of H americanum has been reported from these regions. A ovale has been identified as a vector for H canis in South America. It was previously thought that H canis did not infect canids in North America, despite the presence of R sanguineus, but molecular evidence has recently emerged that suggests otherwise. Still, ACH remains the more severe and more common form of hepatozoonosis in the New World.
In general, immunocompetent dogs appear to tolerate infection with H canis very well. Although life-threatening infections have been reported, clinical signs associated with H canis infection are most often subclinical to mild. However, H americanum causes severe clinical signs in most dogs, with death often occurring within 1–2 yr without supportive therapies.
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, presumably due to severe inflammation within muscle and sometimes along bone, 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°F (39.3°–41°C) and is unresponsive to antibiotics. Longterm sequelae include glomerulonephritis and amyloidosis. H canis tissue stages reside within bone marrow, lymph nodes, and spleen. Unlike in dogs with ACH, dogs infected with H canis typically do not appear painful at presentation; in dogs with overt disease, nonspecific symptoms including fever, lethargy, and depression may be seen.
In dogs with ACH, 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 common. The platelet count is typically normal to high. 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 ACH is made by finding rare gamonts in peripheral blood leukocytes (using Romanowsky-type stains) or identifying pathognomonic "onion skin" cysts or pyogranulomas in stained sections of biopsied muscle sample. Muscle biopsy, although invasive, is considered the gold-standard method for diagnosing ACH, because parasite and parasite-induced lesions are often extensively distributed throughout muscle tissue (especially in areas with observable atrophy). However, in some dogs, multiple or sequential biopsies may be necessary to detect the organism.
Unlike in H americanum infections, parasitemia in dogs with clinical H canis infection is often quite high, and a diagnosis can readily be achieved by microscopic examination of stained blood films to visualize parasite-containing leukocytes. The most common abnormality on bloodwork in dogs infected with H canis is anemia. Serum chemistry abnormalities may be similar to those seen in dogs with ACH. Hepatitis, pneumonia, and glomerulonephritis associated with H canis meronts have been reported postmortem in some animals with extremely high parasitemia. Although experimental serologic assays have been developed to detect both H americanum and H canis infections, none is available commercially. PCR methods developed to detect circulating Hepatozoon are available through several different institutions (including Auburn University and North Carolina State University), although they may lack sensitivity in H americanum infections because of typically low levels of parasitemia. These molecular 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 pathogenicity and/or life cycle patterns will be found to cause disease in dogs.
Hepatozoonosis is generally considered a lifelong infection in dogs. No known therapeutic regimen completely clears the body of the organism. In the past, treatment of ACH has been frustrating, because most dogs showed only temporary improvement with frequent relapses within 3–6 mo and death within 2 yr of diagnosis. Remission of clinical signs can usually be achieved through a 14-day course of 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/day, PO). Unfortunately, remission with this therapy has often been short-lived, and dogs frequently relapse within 2–6 mo. However, an adjunctive treatment using decoquinate 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 dosage of 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 marked improvement in the prognosis for dogs with ACH. NSAIDs 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.
H canis infections are treated with imidocarb dipropionate, twice monthly, at 5–6 mg/kg, SC, until the parasite is no longer evident in blood smears for 2–3 consecutive months. Prognosis often depends on the degree of parasitemia; dogs with low parasitemia typically respond well to treatment, whereas those with high parasitemia may not, especially if afflicted by concurrent illness.
Preventing 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. Additionally, dogs diagnosed with hepatozoonosis should not be bred because transplacental transmission of H canis has been documented, and although vertical transmission of H americanum has not been reported, the possibility should not be disregarded.
There is no known zoonotic risk with hepatozoonosis.