Canine-canine Hepatozoonosis-pathophysiology,diagnosis And Treatment

Vol.19, No. 1 January 1997

Continuing Education Article

FOCAL POINT ★In the United States, hepatozoonosis is most commonly diagnosed by muscle biopsy.

KEY FACTS ■ In the United States, hepatozoonosis is no longer limited to the Texas Gulf Coast region. ■ There are differences between the clinical syndrome of hepatozoonosis in the United States and that in other parts of the world; clinical signs in the United States include muscle pain, ocular discharge, cachexia, and leukocytosis. ■ Common abnormal laboratory values in American hepatozoonosis include marked leukocytosis, hypoglycemia, hypoalbuminemia, and low blood urea nitrogen. ■ Treatment with oral trimethoprim–sulfadiazine (15 mg/kg every 12 hours), pyrimethamine (0.25 mg/kg every 24 hours), and clindamycin (10 mg/kg every 8 hours) may induce remission, but relapses are common.

Canine Hepatozoonosis: Pathophysiology, Diagnosis, and Treatment Auburn University

Hebrew University of Jerusalem

Nancy Vincent-Johnson, DVM Douglass K. Macintire, DVM, MS

Gad Baneth, DVM

T

he causative agent for canine hepatozoonosis is Hepatozoon canis, a protozoal organism from the phylum Apicomplexa.1 Since its discovery in India in 1905,2 the organism has been reported in dogs in many regions of the world, including Africa,3,4 southern Europe,5–8 Israel,9,10 Japan,11 Malaysia,12 the Philippines,13 and the United States.14 In addition to infecting dogs, various stages of H. canis or closely related, undetermined species have been reported in coyotes,15 bobcats,16 and ocelots17 in the U.S.; foxes in Portugal18; African lions3,19,20; jackals, hyenas, cheetahs, a leopard,3 and an impala21 in South Africa; and domesticated cats throughout the world.22–27 There is one report of an organism resembling H. canis in the blood of a human from the Philippines.28 Other species of Hepatozoon infect rodents,29 raccoons,30 squirrels,31 and reptiles.32

LIFE CYCLE AND TRANSMISSION H. canis is a two-host organism. The definitive host is the brown dog tick (Rhipicephalus sanguineus), and the intermediate host is the dog.33 While feeding on an infected dog, nymphal ticks ingest gametocytes in the dog’s neutrophils and monocytes (Figure 1). Two gametocytes fuse in the gut of the tick to form an ookinete. The ookinete penetrates the gut wall and enters the hemocoelom, where it matures into an oocyst as the tick molts to the adult stage. Numerous sporocysts are formed in the developing oocyst. In each sporocyst, 12 to 24 sporozoites form. Unlike the parasites that cause most other tick-borne diseases, these organ-

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isms remain in the hemocoelom of the tick and do not sis in the U.S. compared with that which occurs in the migrate to the salivary glands or mouthparts. The orrest of the world. These differences include the severity ganism is transmitted by ingestion of an infected tick, and type of clinical signs, clinical laboratory findings, not by a tick bite. Once the tick is ingested, the sporothe frequency with which gametocytes are evident, and zoites in the tick are released and penetrate the intestithe tissue stages of the organism. The differences in the nal tract of the dog. The organisms are then carried by clinical signs and tissue stages associated with canine blood or lymph to mononuclear phagocyte cells of the hepatozoonosis in the U.S. indicate that the causative spleen, bone marrow, muscle, liver, and lung. After inagent may be a species of Hepatozoon that is distinct from H. canis found in the rest of the world. vading these cells, the organisms form schizonts, which undergo asexual division. Merozoites formed in schiAMERICAN HEPATOZOONOSIS zonts are released and invade additional cells. After Canine hepatozoonosis was first reported in the U.S. multiple cycles of schizogony, merozoites invade leukoin 1978 near the Gulf Coast region of Texas.14 Later recytes and produce gamonts in them, completing the ports involved dogs originating from the neighboring life cycle. states of Oklahoma 40 and Louisiana. 41 In addition, Oocysts of H. canis have been reported in Haema34 physalis longicornis and Hae. flavas ticks in Japan as many cases have been reported in Alabama and Georgia well as Amblyomma habraeum, A. marmoreum, R. apin recent years; the disease is apparently spreading geopendiculatus,35 and R. simus 3 ticks in Africa. Structures graphically.42,43 Although hepatozoonosis has traditionally been conresembling H. canis oocysts have been identified recently in A. maculatum ticks removed from a dog with clinsidered to be an opportunistic infection, immunosupical signs of hepatozoonosis in the U.S.36 pression or concurrent illness is apparently not necesExperimental transmission of H. canis via ingestion sary for the organism to cause disease in the U.S. In a of infected ticks has been reported.3,37,38 In the only retrospective study, secondary disease entities were study performed in the U.S., immunosuppressed reidentified in only 50% of infected dogs.42 In some search dogs were infected via ingestion of exposed R. sanguineus ticks; attempts to infect the dogs by allowing ticks to feed on them were unsuccessful. 38 Other species of Hepatozoon have been transmitted via ingestion of cysts present in intermediate hosts. 32 It has been speculated that H. canis may be transmitted via ingestion of infected tissue, but no experimental data support this hypothesis. Vertical transmission of H. canis has been reported. Puppies born to infected bitches and raised in a tick-free environment demonstrated gametocytes shortly after birth.39 There are major dif- Figure 1—Life cycle of H. canis in the dog and the R. sanguineus tick. (From Craig TM: Hepatoferences in the syn- zoonosis, in Greene CE [ed]: Infectious Diseases of the Dog and Cat. Philadelphia, WB Saunders Co, 1990, p 779. Reproduced with permission.) drome of hepatozoonoMONONUCLEAR PHAGOCYTE CELLS ■ INTERMEDIATE HOSTS ■ VERTICAL TRANSMISSION

The Compendium January 1997

households, several dogs were diagnosed as having the disease. In most of these cases, the dogs were unrelated; an inherited susceptibility to the organism or a common underlying immunosuppression was unlikely. Although it has been reported that dogs greater than 4 to 6 months of age are resistant to experimental infection, age is apparently not an important factor in the expression of natural dis- Figure 2—A dog with American hepatozoonosis. Note the ease; clinical hepatozoonosis stance associated with muscle pain, the severe muscle atrooccurs in dogs of various phy, and the bilateral ocular discharge. ages.

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Mucopurulent ocular discharge is common and results in the appearance of matted eyes. This discharge is frequently but not always associated with decreased tear production; it may come and go with the fever spikes. Owners often report this as the first noticeable sign during a relapse. Despite the illness, dogs often maintain a fair appetite. Weight loss associated with chronic cachexia, muscle atrophy, and emaciation is common. Polyuria and polydipsia may be evident. Transient bloody diarrhea occasionally occurs.

Clinical Signs Dogs are typically presentLaboratory and ed with gait abnormalities Radiographic Findings that range from stiffness to The most outstanding complete recumbency, genlaboratory finding is a high eralized pain, and deteriorawhite blood cell count, tion of body condition. The consisting primarily of an most common findings on increased number of segphysical examination are mented neutrophils. White fever, generalized pain or hyblood cell counts generalperesthesia, muscle atrophy, ly range from 20,000 to weakness, depression, reluc200,000 cells/mm3; means tance to rise, and mucoof 76,807 44 and 85,700 purulent ocular discharge have been reported. 42 Al(Figure 2). Body temperathough the leukocytosis is ture ranges from normal usually characterized by mat o 106˚F (41˚C); fevers ture neutrophilia, a left shift of 104˚F to 105˚F are commay be evident. On a blood mon. Temperature tends to smear, many of the segfluctuate with waxing and mented neutrophils may apwaning of clinical signs. pear hypersegmented. A deMuscle pain results from creased platelet count is rare inflammation associated unless concurrent infection with stages of the organism. The pain may result in in- Figure 3—Periosteal proliferation of the femurs in a dog with Ehrlichia canis or E. ability or reluctance to rise, with American hepatozoonosis. Lesions may be dramatic, platys is present; in fact, the platelet count is sometimes stiffness of gait, and hyperes- as in this case, with smooth laminar thickening. elevated. Mild to moderate thesia. The dog may display normocytic, normochroa so-called master’s-voice mic, nonregenerative anemia is typical. stance in an attempt to guard the cervical region. With On serum chemistry evaluation, a mild elevation in chronic disease, muscle atrophy becomes apparent. All serum alkaline phosphatase is usually present. Creatine muscles may be affected, including those of the pelvic phosphokinase is normal in most cases of hepatozoonoand thoracic limbs, muscles of mastication, and lumbar sis. Blood glucose is frequently decreased, in the range muscles. Weakness is secondary to muscle atrophy. GAIT ABNORMALITIES ■ OCULAR DISCHARGE ■ CHRONIC CACHEXIA

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of 40 to 60 g/dl and occadogs in one study 44; they sionally as low as 5 g/dl. The were seen in 0 of 22 dogs in low glucose is a laboratory another study.42 When preartifact caused by increased sent, the infected cells rarely metabolism in vitro by the exceed 0.1% of the leukoelevated white blood cell cytes; it may be necessary to numbers. If blood is drawn examine several thousand in sodium fluoride tubes, leukocytes before finding the glucose is usually within an infected one. Buffy coat the reference range. The smears increase the chance blood urea nitrogen (BUN) of detecting gametocytes. is often below the reference Gametocytes apparently exit range. Some researchers atleukocytes rapidly after tribute this finding to deblood is drawn, leaving becreased protein intake.42 The Figure 4—Gametocytes of H. canis in canine neutrophils. hind an empty capsule that typical decrease in albumin The intracellular inclusions are oblong and average 11.4 by is easily missed. A delay in is attributed to decreased 5.3 µm in size. The intensity of the parasite nucleus varies making the blood smears protein intake, chronic in- with the type of stain used. (May-Grunwald stain, original thus may hinder the detecmagnification ×400) flammation, or renal loss. tion of gametocytes. Hyperglobulinemia is an Various stains have been infrequent finding, but used in attempts to make serum protein electrophothe infected cells stand out resis may demonstrate an better. Of the three stains increase in the α 2- and βevaluated in one study,45 a globulin range. Because modified Wright-Giemsa acute-phase proteins are stain demonstrated the least located in this region, it is morphologic differentiation likely that this increase repof the parasite from the resents a switch to produchost cell; the capsule of the tion of these proteins in gamont stained clear to response to the persistent inlight blue, with slight or flammatory changes associno staining of the nucleus. ated with tissue stages of the Although Giemsa stain organism. The impression of revealed the nucleus of the decreased BUN, albumin, Figure 5—H. canis cyst in the skeletal muscle of a dog with parasite, it stained with the and glucose suggests hepatic American hepatozoonosis. (H&E stain, original magnifica- same intensity as the hostfailure; however, bile acids tion ×200) cell nucleus, making the (fasting and postprandial) two difficult to differentiare usually within reference ate. The best procedure ranges or slightly elevated. evaluated for differentiating parasite from host cell was Radiography frequently demonstrates periosteal prothe use a naphthol-ASD-chloroacetate stain followed liferation of various bones, including the ilium, humby a Giemsa stain. The cytoplasm of normal neutroerus, radius, ulna, femur, tibia, fibula, and vertebrae phils contains red granules that are absent in infected (Figure 3). This proliferation may be subtle or dramatic cells. After the Giemsa stain, there was a difference in and ranges from irregularity to a smooth laminar thickthe intensity of the staining of the parasite’s nucleus ening. Proliferation occurs at the attachments of muscle compared with that of the host cell. and probably results from the severe myositis that can Because of the infrequency with which gametocytes develop. are evident, even with buffy coat smears, muscle biopsy is a more consistent method of obtaining a definitive Diagnosis diagnosis. The American form of hepatozoonosis differs In dogs with American hepatozoonosis, gametocytes significantly from hepatozoonosis elsewhere in the are infrequently found on peripheral blood smears (Figworld by the myositis and the stages of the organism ure 4). Gametocytes were evident in 9 of 15 infected seen in skeletal muscle.46 LOW GLUCOSE ■ HYPERGLOBULINEMIA ■ SEVERE MYOSITIS

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Muscle lesions consist of granulomatous vasculitis. large cysts, pyogranulomas, Roughening and thickenand myositis. The cysts are ing of bone surfaces may be round to ovoid and range apparent. Histologic examifrom 250 to 500 µm in nation may demonstrate diameter (Figure 5). The bone exostosis with intracenter of the cyst usually trabecular fibrosis and incontains a single, round, creased osteoblastic and centrally located basophilic osteoclastic activity. Surnucleus but occasionally rounding periosteum and contains numerous small, fascia exhibit pyogranuloround, basophilic bodies mas, with periosteal vessels grouped together. Surrounddemonstrating inflammaing the nucleus or round tion and mineralization. basophilic bodies are con- Figure 6—Pyogranuloma in the skeletal muscle of a dog Occasional findings include centric layers of slightly with American hepatozoonosis. (H&E stain, original mag- pulmonary congestion, basophilic, fine laminar nification ×100) splenic coagulative necrosis, membranes with a so-called lymphadenopathy, and cononion-skin appearance. In gestion of the gastric mumost cases, no inflammatory response is associated with cosa. Renal lesions that may be present consist of multhe cysts. These cystic structures have not been reporttifocal pyogranulomas, lymphoplasmacytic interstitial ed outside the U.S. nephritis, and mesangioproliferative glomerulonephriThe pyogranulomas consist of large accumulations of tis. In chronic hepatozoonosis, amyloid deposits may macrophages and neutrophils, many of which contain be apparent in the spleen, lymph nodes, small intesround, intracellular parasites (Figure 6). Myositis with tine, liver, and kidney. Unless amyloidosis is present, muscle atrophy, necrosis, and infiltration of inflammaliver lesions are usually minimal. Schizonts with the tory cells between muscle fibers is a frequent finding. characteristic wheel-spoke pattern typically seen in the The most common muscles examined by biopsy are the spleen, lymph nodes, lungs, and liver of infected dogs biceps femoris, semitendinosus, and the lumbar musfrom countries outside the U.S. have not been obcles. Lesions have been found in clinically ill dogs; cysts served.33 have also been seen in biopsies from dogs in clinical reTreatment mission.44 These cysts are believed to represent resting Treatment for American hepatozoonosis consists of stages of the organism, like the tissue cysts of Toxoplasma gondii.47 specific therapy using antiprotozoal drugs and palliative Bone marrow aspirates usually demonstrate granulotherapy with nonsteroidal antiinflammatory drugs cytic hyperplasia with an increased myeloid:erythroid (NSAIDs). Because of the waxing and waning nature of ratio. Lymph node aspirates may exhibit lymphoid the clinical signs, the efficacy of treatment is difficult to hyperplasia. Neither procedure is useful in making a judge. Imidocarb dipropionate is commonly used in definitive diagnosis because the organisms are not typiother countries; in the U.S., this drug is classified as cally seen in these samples. investigational and is not readily available. The agent Necropsy of infected dogs reveals the large cysts not clears parasitemia but does not necessarily produce clinonly in the skeletal muscle but also in the cardiac musical improvement. In one case, clinical improvement cle, intestinal smooth muscle, pancreas, spleen, lymph was associated with the use of diminazene aceturate, node, liver, skin, and lung. Other lesions that are evibut the effect may have been coincidental to spontadent on necropsy include pyogranulomas in the skeletal neous remission.14 An excellent initial response was associated with the use of the coccidiostat toltrazuril; muscle, cardiac muscle, pancreas, tongue, lymph node, however, the drug failed to prevent relapse in most dogs and kidney. Grossly, the pyogranulomas may appear and is no longer available in the U.S. as multiple, 1- to 2-mm diameter, white-to-tan foci Drugs that are effective against T. gondii also have diffusely scattered throughout these organs. Infiltrates efficacy in treating American hepatozoonosis. A comof macrophages and neutrophils have been evident in bination of a sulfonamide with pyrimethamine and alveoli of the lungs. Vascular changes in various organs clindamycin has resulted in remission of clinical signs. include fibrinoid degeneration of vessel walls, mineralThe following oral dosages were given for 14 days: ization and proliferation of vascular intima, and pyoMUSCLE LESIONS ■ BONE MARROW ASPIRATES ■ LIVER LESIONS

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trimethoprim–sulfadiazine at 15 mg/kg every 12 hours, pyrimethamine at 0.25 mg/kg every 24 hours, and clindamycin at 10 mg/kg every 8 hours.42 Like the other drugs, this combination is apparently not effective against the resting stages of the organism and thus does not prevent relapses. New antiprotozoal agents show some promise in preventing relapses. Palliative therapy with aspirin or other NSAIDs has been useful in relieving fever and pain. The dosage and frequency should be adjusted for each dog based on response. Although corticosteroids offer relief, they may exacerbate the disease in the long run.

Prognosis The prognosis for patients with American hepatozoonosis is guarded. A few dogs may undergo spontaneous remission and exhibit no further clinical signs. After successful treatment, some dogs become clinically normal, with resolution of leukocytosis and serum chemistry abnormalities. Most dogs tend to relapse 3 to 6 months after treatment. In some dogs, clinical signs associated with relapse are less severe than the initial episode. In many of these dogs, leukocytosis and chemistry abnormalities return despite exhibition of few clinical signs. Many dogs with hepatozoonosis exhibit proteinuria secondary to glomerulonephritis or amyloidosis. These dogs develop classical signs of the nephrotic syndrome with hypoalbuminemia and hypercoagulability. Death frequently results from thromboembolism in the pulmonary vasculature or gastrointestinal tract. In two studies of American hepatozoonosis (totaling 37 dogs), 60% of the subjects died or were euthanatized because of chronic wasting, severe pain, or renal failure.42,44 The average survival time for those that died was 10.5 months. Of the 11 dogs that were alive at the end of studies, seven became asymptomatic and four continued to have episodes of clinical disease. The remaining dogs were lost to follow-up. HEPATOZOONOSIS BEYOND THE UNITED STATES Outside the U.S., H. canis infections range from subclinical to severe, life-threatening disease. Gametocytes of H. canis have been reported as incidental findings in apparently healthy animals11 and in animals with concurrent infection (e.g., ehrlichiosis10 or toxoplasmosis48). A few dogs exhibit high parasitemia and severe disease characterized by lethargy, fever, anorexia, weight loss, anemia, neutrophilia, hyperglobulinemia, hypoalbuminemia, and elevations in creatine kinase and alkaline phosphatase activity. In one report from Israel, parasitemia in two dogs

ranged from 60% to 90% of peripheral neutrophils.9 Both patients were positive for antibodies against E. canis; this factor may have played a role in enabling the H. canis to disseminate. One of the dogs died after continued weight loss, muscle wasting, and the development of icterus. The other dog returned to normal 3 months after initial admission and antiprotozoal treatment. No gametocytes were detected in blood smears at the time. A recent seroepidemiologic survey demonstrated that more than 33% of dogs in Israel have antibody titers of at least 1:32 against H. canis.49 Only 1% of dogs surveyed were parasitemic when samples were taken. This indicates a high degree of exposure and subclinical infection with H. canis in Israel. In Nigeria, H. canis is reportedly the most prevalent hematozoan parasite in dogs; 22% of the dogs examined at one institute exhibited circulating gametocytes.4 A survey of dogs at veterinary clinics in Malaysia demonstrated an incidence of 1.2% based on the observation of gametocytes in blood smears.12 In one region in Spain, a survey in 1990 demonstrated a parasitemia rate of 30% in dogs.5

Clinical Signs Although a number of dogs with hepatozoonosis may be asymptomatic or exhibit clinical signs attributed to concurrent infection, several reports describe various clinical presentations. The most commonly reported clinical signs are fever, pale mucous membranes, depression, anorexia, and weight loss. Less commonly reported signs include lymphadenopathy, poor haircoat or skin condition, bilateral mucopurulent ocular or nasal discharge, hyperesthesia, weakness of the hindlimbs, petechiae, ecchymoses, and epistaxis. In some cases, the dogs had concurrent ehrlichiosis, leishmaniasis, babesiosis, distemper, or other infections; it was difficult to determine which disease was responsible for the various clinical signs.5 Laboratory and Radiographic Findings Most dogs with hepatozoonosis outside the U.S. have a white blood cell count that is within the reference range. Extreme leukocytosis occurs in some cases8,9 but is less common than in dogs with American hepatozoonosis. Anemia, which is sometimes severe, is a common finding. Thrombocytopenia and proteinuria have been reported. Reports of serum chemistry results are sparse. The two highly parasitemic dogs from Israel reportedly had hyperglobulinemia, hypoalbuminemia, and elevated creatine kinase and alkaline phosphatase activity.9 Mild to severe proteinuria (indicating possible glomerulonephritis) was found in 8 of 11 dogs in a study from Greece; otherwise, secondary renal disorders have not been reported.6

PALLIATIVE THERAPY ■ PROTEINURIA ■ CONCURRENT INFECTION

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There is one report of radiographic lesions associated with hepatozoonosis outside the U.S. 11 Gametocytes of H. canis were evident in blood smears of a dog after surgery for intervertebral disk protrusion. Periosteal new bone formation of the radii, ulnae, ilia, and femur was seen 23 days after surgery but had not been noted before surgery. No clinical signs attributed to H. canis were evident. In another study, seven dogs were radiographed but exhibited no periosteal lesions.5

Figure 7—Schizont of H. canis in the spleen of a dog from Israel. The wheel-spoke pattern is typical of schizonts in the spleen and other organs of dogs with disseminated hepatozoonosis outside the U.S. (H&E stain, original magnification X400)

Diagnosis Non-American H. canis infection is diagnosed by observing gametocytes on blood smears (Figure 4). The gametocytes are found as intracellular inclusions in neutrophils and monocytes. The size reportedly averages 11.4 µm long by 5.39 µm wide.50 Parasitemia can vary from less than 1% to more than 90% of the neutrophils being infected.6,9 In most cases, parasitemia is low and affects approximately 1% of the neutrophils. On necropsy, schizonts with the characteristic wheelspoke pattern can be found in the spleen, liver, lymph nodes, kidneys, lungs, pancreas, and bone marrow (Figure 7). Although 6 of the 11 dogs from Greece reportedly had signs of muscle pain, no evidence of muscular parasitism was reported. The presence of organisms in skeletal muscle and the large cysts seen in American dogs with hepatozoonosis have not been reported in dogs outside the U.S. An indirect immunofluorescence test has been developed in Israel to detect antibodies against H. canis.51 The test uses gametocytes as the source of antigen. The test will apparently be useful in diagnosing hepatozoonosis, especially in dogs with very low or intermittent parasitemia. Treatment The most commonly reported drug used to treat hepatozoonosis is imidocarb dipropionate. This agent is typically given subcutaneously at a dose of 5 mg/kg. Some clinicians pretreat with atropine at 0.04 mg/kg to limit the anticholinesterase effect.5 In Nigeria, imidocarb cleared H. canis gametocytes from the blood in 98% of dogs within 24 hours of a single treatment.52 The gametocytes frequently reappeared within 6 weeks.

At the Hebrew University of Jerusalem, Koret School of Veterinary Medicine, the standard protocol is treatment with imidocarb at 5 mg/kg subcutaneously every 14 days until no parasites are evident on blood smears. Treatment may continue for 60 days or more before elimination of gametocytes is complete. Tetracyclines, including doxycycline and minocycline, are often used in conjunction with imidocarb. Diminazene aceturate has been used but has not proven effective in eliminating parasitemia.9

Prognosis Although most dogs with hepatozoonosis recover, the disease may become disseminated and fatal in very young animals and in animals with underlying immunosuppression. Although mortality is uncommon in dogs with low H. canis parasitemia, dogs that develop high parasitemia have severe disease and a low survival rate. HEPATOZOONOSIS IN CATS Hepatozoonosis has been reported in domesticated cats in India,22 Nigeria,23 South Africa,24 the U.S.,25 and Israel.26,27 In a survey of 100 necropsies of cats in Israel, 36 exhibited schizonts of a Hepatozoon species in the myocardium.26 Of the cats surveyed, 50 had been submitted to the laboratory for rabies examination and 50 were healthy strays that had been used in laboratory demonstrations. No parasites were evident in the peripheral blood, spleen, or lymph nodes of these cats. In a cat from Israel, hepatozoonosis was diagnosed by the presence of gametocytes on a blood smear.27 The cat exhibited signs of weakness, hypersalivation, superficial ulceration in the lingual mucosa, mild gingivitis, halitosis, and lymphadenopathy. The body temperature was normal, and the only abnormal laboratory values were lymphopenia and elevated lactate dehydrogenase and creatine phosphokinase. The cat recovered after daily treatment with oral doxycycline at 5 mg/kg for 10 days. Titers against H. canis were 1:128 at presentation and 1:64 one year later. Organisms resembling a species of Hepatozoon were reported in the liver of a cat in the U.S.25 The cat originated from Hawaii and became ill shortly after arrival

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in California. Clinical signs included weight loss, ulcerative glossitis, intermittent anorexia, pyrexia, progressive anemia, and serous oculonasal discharge. Laboratory abnormalities included extreme leukocytosis, severe anemia, azotemia, and icterus. On necropsy, numerous cigar-shaped organisms were found in the portal areas of the liver but not elsewhere. Nondomesticated felids (including lions, cheetahs, bobcats, and ocelots) in Africa and the U.S. are known to harbor Hepatozoon species. In various surveys, as many as 100% of lions have been infected with a Hepatozoon species in the peripheral blood or the myocardium.19,20,35 It is currently not known whether the infections in domesticated and wild cats are caused by H. canis or another Hepatozoon species.

SUMMARY Infection with H. canis is manifested in various clinical presentations. In the U.S., hepatozoonosis is often a severe, life-threatening disease characterized by chronic wasting. Glomerulonephritis, amyloidosis, and the nephrotic syndrome are common sequelae to the disease. Diagnosis usually requires muscle biopsy because of the infrequency with which gametocytes are evident in the blood. Muscle lesions are unique to American canine hepatozoonosis and consist of large cystic structures, pyogranulomas, and pyogranulomatous myositis. Outside the U.S., the rate of exposure to H. canis is high in some regions; most infections apparently are subclinical. Gametocytes of H. canis are often evident in the blood of apparently asymptomatic dogs and dogs with other infectious diseases. A few dogs may develop a more severe disease that is sometimes fatal. These dogs are typically young, immunosuppressed, or affected by concurrent disease. Hepatozoon infections have been recognized in cats. The unique clinical syndrome in American dogs with hepatozoonosis suggests the presence of a strain or subspecies of the H. canis organism distinct from that which causes hepatozoonosis in domesticated dogs worldwide. Further research is needed to clarify the differences reported here.

About the Authors Drs. Vincent-Johnson and Macintire are affiliated with the Department of Small Animal Surgery and Medicine, College of Veterinary Medicine, Auburn University, Auburn, Alabama. Dr. Baneth is with the Koret School of Veterinary Medicine, Hebrew University of Jerusalem, Rehovot, Israel.

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REFERENCES 1. Levine ND: The Protozoan Phylum Apicomplexa. Boca Raton, FL, CRC Press, 1988, pp 129–133. 2. Bentley CA: Preliminary note on a leukocytozoan of the dog. Br Med J 1:988, 1905. 3. McCully RM, Basson PA, Bigalke RD, et al: Observations on naturally acquired hepatozoonosis of wild carnivores and dogs in the Republic of South Africa. Onderstepoort J Vet Res 42:117–134, 1975. 4. Ezeokoli CD, Ogunkoya AB, Abdullahi R, et al: Clinical and epidemiological studies on canine hepatozoonosis in Zaria, Nigeria. J Small Anim Pract 24:455–460, 1983. 5. Jauregui Latorre E, Lopez Giron M: Canine hepatozoonosis. Vet Int 7:30–38, 1995. 6. Kontos V, Koutinas A: Canine hepatozoonosis: A review of 11 naturally occurring cases. Bull Hellen Vet Med Soc 41: 73–81, 1990. 7. Fischer S, Hartmann K, Gothe R: Hepatozoon canis: Eine importierte parasitäre Infektion bei Hunden. Tierarztl Prax 22:172–180, 1994. 8. Hervas J, Carrasco L, Gomez-Villamandos JC, et al: Acute fatal hepatozoonosis in a puppy: Histopathological and ultrastructural study. Vet Rec 137:518–519, 1995. 9. Baneth G, Harmelin A, Presentey BZ: Hepatozoon canis in two dogs. JAVMA 206:1891–1894, 1995. 10. Elias E, Homans PA: Hepatozoon canis infection in dogs: Clinical and hematological findings—Treatment. J Small Anim Pract 29:55–62, 1988. 11. Murata T, Shiramizu K, Hara Y, et al: First case of Hepatozoon canis infection of a dog in Japan. J Vet Med Sci 53(6):1097–1099, 1991. 12. Rajamanickam C, Wiesenhutter E, Zin FMD, Hamid J: The incidence of canine haematozoa in peninsular Malaysia. Vet Parasitol 17:151–157, 1984. 13. Novilla MN, Kwapien RP, Peneyra RS: Occurrence of canine hepatozoonosis in the Philippines. Proc Helminthol Soc Washington 44(1):98–101, 1977. 14. Craig TM, Smallwood JE, Knaver KW, McGrath JD: Hepatozoon canis infection in dogs: Clinical, radiologic, and hematologic findings. JAVMA 173(8):967–972, 1978. 15. Davis DS, Robinson RM, Craig TM: Naturally occurring hepatozoonosis in a coyote. J Wildl Dis 14:244–246, 1978. 16. Lane JR, Kocan AA: Hepatozoon sp. infection in bobcats. JAVMA 183:1323–1324, 1983. 17. Mercer SH, Jones LP, Rappole JH, et al: Hepatozoon sp. in wild carnivores in Texas. J Wildl Dis 24:574–576, 1988. 18. Conceicao-Silva FM, Abranches P, Silva-Pereira CD, Janz JG: Hepatozoonosis in foxes from Portugal. J Wildl Dis 24:344–347, 1988. 19. Averbeck GA, Bjork KE, Packer C, Herbst L: Prevalence of hematozoans in lions (Panthera leo) and cheetah (Acinonyx jubatus) in Serengeti National Park and Ngorongoro Crater, Tanzania. J Wildl Dis 26:392–394, 1990. 20. Dubey JP, Bwangamoi O: Microbesnoitia leoni Bwangamoi, 1989, from the African lion (Panthera leo) redetermined as a junior synonym of Hepatozoon canis (James, 1905) Wenyon, 1926. J Parasitol 80(2):333–334, 1994. 21. Basson PA, McCully RM, Bigalke RD, van Niekerk JW:

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