Article #5 CE Feline Cytauxzoonosis

Peter J. Bondy, Jr, DVM, MS, DACVIM Leah A. Cohn, DVM, PhD, DACVIM Marie E. Kerl, DVM, DACVIM, DACVECC University of Missouri

ABSTRACT: felis is a protozoal organism transmitted to through a tick bite. Region- ally restricted to the south central and southeastern , C. felis infection of domestic cats is usually fatal.The parasite life cycle includes both a tissue and an erythro- cytic phase.The clinical disease course is rapid, with onset of fever, lethargy, and anorexia 5 to 20 days after infection and death within a week of initial signs. Leukocytosis, , icterus, and elevated liver enzymes are usually present. Definitive diag- nosis is based on microscopic identification of parasites. Effective medical therapy remains elusive, although several cats have reportedly survived.

ytauxzoon felis is a protozoal organism schizont phase of the genus occurs in that causes fatal illness in domestic lymphocytic cells.3 The infected macrophage cats. It is related to other Cytauxzoon cells occlude venules in the liver, spleen, lung, C 1 spp of African ungulates and was first recog- and lymph nodes (Figure 2). The schizont nized in Missouri in 1976.1 Geographically phase is most closely associated with clinical limited primarily to the south central and disease, and the degree of schizogony is southeastern United States (Figure 1), C. felis reflected in the severity of illness.4 In domestic seems to infect only and therefore cats, the schizont burden is extensive, whereas it poses no zoonotic or agricultural risk.2 Diag- is usually small and brief in mildly affected nosing cytauxzoonosis in cats is based on com- species such as the .5 patible clinical signs and identifying the of the schizonts results in formation organisms in tissue or blood. No form of ther- of merozoites.6 Merozoites are released when apy has been proven effective, and most ill cats the infected macrophage ruptures; these die despite supportive and/or antimicrobial merozoites undergo endocytosis by erythro- treatment. cytes. In erythrocytes, these forms are referred C. felis is a protozoan organism belonging to to as piroplasms. Although visualization of the order and the family Theileri- piroplasms on a peripheral blood smear is the idae. Like its relatives in the genus Theileria, most direct and simple way to diagnose infec- C. felis exists in distinct erythrocytic and non- tion, it is the schizont phase that leads to erythrocytic life phases. After infection, the or- venous congestion, thrombotic disease, organ ganism undergoes an asexual failure, and ultimately death.4,7,8 Piroplasms Send comments/questions via email reproductive phase referred to may persist for life after recovery from schi- [email protected], as schizogony. Schizonts of C. zogony in both domestic and nondomestic fax 800-556-3288, or web felis occur in mononuclear cats without apparent clinical consequences CompendiumVet.com phagocytic cells, whereas the for infected animals.9,10

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develop into their next life stage in an intermediate host, such as ticks, to produce the virulent schizont form. Therefore, transfusion from cats that have recov- ered to ones that are naive would not result in illness even if erythrocytes contain piroplasms.10,19 However, transfusion from recently infected cats during clinical illness or just before onset of illness can transmit infec- tion because circulating monocytes can contain schiz- onts.7,19 Blood-donor cats should be in good health, kept free of ectoparasites, and ideally housed indoors to minimize this very small risk. Close contact between cats in the absence of tick vectors does not Figure 1. US states with confirmed cases (in yellow) of pose a risk of disease transmission.18 Although multi- C. felis infection. ple cats within a household are commonly infected, this circumstance is more likely related to common exposure to infected tick populations than to direct PROPOSED LIFE CYCLE AND -to-cat contact. TRANSMISSION Although its natural life cycle is not completely CLINICAL PRESENTATION understood, C. felis is a tickborne disease.11 are Feline cytauxzoonosis is most commonly reported in persistent carriers of this organism after infection and middle-aged cats, although it can occur at any age.8,10 are the presumed reservoir for C. felis.2,12 Ticks presum- Sex and breed predilections have not been identified.8 ably transmit the organism from one cat to another by Outdoor cats are more likely to acquire this disease, pre- feeding.11 The only tick that has been experimentally sumably because of increased exposure to tick vectors.8,10 demonstrated to be a competent vector of C. felis is Der- The greatest risk of infection seems to occur in the macentor variabilis, although many other species of ticks spring and early summer, presumably when the tick vec- may feed on wild or domestic cats.11,13 Although domes- tors are most active. Sixty-one of 81 (75%) cases evalu-

Only felidae are susceptible to infection with C. felis. tic cats generally succumb to infection and are consid- ated at the University of Missouri Veterinary Medical ered terminal hosts, the eastern bobcat (Lynx rufus Diagnostic Laboratory and Veterinary Medical Teach- rufus) usually develops mild or subclinical infection.2,5,12 ing Hospital over the past 5 years were seen from May Extensive investigation has shown that nonfelidae through July. species, including immunodeficient mice, cannot be The onset of clinical disease occurs 1 to 3 weeks infected.2 However, both clinical and nonclinical infec- after infection.4,18 Clinical signs are nonspecific and tion has been demonstrated or at least strongly sus- include anorexia, lethargy, dyspnea, icterus, and pected in several felidae, including a captive white tiger pallor.1,3,4,9,10,17 Physical examination usually demon- (Panthera tigris), Florida panthers (Felis concolor coryi), a strates pyrexia (often marked), but hypothermia is Texas cougar (Felis concolor), and cheetahs (Acinonyx common in moribund cats.1,8–10 Tachypnea and tachy- jubatus).14–17 cardia are typical, with or without overt respiratory Infection can be accomplished experimentally by distress.4,9 Abdominal palpation often reveals inoculating schizont-containing tissue.18 However, splenomegaly and/or .1,4,8 Altered menta- inoculating erythrocytes that contain piroplasms only tion, vocalization, seizures, and coma may occur in the results in persistent erythroparasitemia without the later stages of disease.18,20 The disease course is rapid, clinical illness that results from the schizont phase of and most cats succumb within 1 week of initial clinical infection.11 It appears that the piroplasms must illness.7,8,21

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Figure 2. Hematoxylin-and-eosin–stained photomicrographs of a histologic section of an infected spleen.

(Original magnification ×10) A splenic vein lined by schizont-laden macrophages in different stages. (Original magnification ×40; courtesy of Dr. Susan Turnquist)

DIAGNOSIS Although historical and physical findings are nonspe- cific, a patient with acute onset of fever, pallor, icterus, and splenomegaly or hepatomegaly in an endemic region should immediately prompt clinicians to suspect cytauxzoonosis. The differential diagnosis might include infection (formerly Haemobar- tonella felis), cholangitis or cholangiohepatitis, immune- mediated hemolytic anemia, retroviral disease sequelae, toxoplasmosis, and feline infectious peritonitis. Diag- nostic testing should be directed toward both confirm- ing the infection and eliminating diagnostic differentials from consideration. Of the routine imaging and initial laboratory tests, only examination of peripheral blood Figure 3. Wright’s-stained peripheral blood smear smears can confirm the diagnosis. Visualizing erythro- exhibiting C. felis (arrows) within erythrocytes. (Original cytic piroplasms is sufficient evidence to confirm infec- magnification ×100) tion. Piroplasms are most often shaped as 1 to 1.5 µm signet rings (Figure 3), but “safety pin” and tetrad forms are also observed, as are chains of organisms resembling cocci.9,17 Although piroplasms are a specific finding, they used to confirm the presence of C. felis8 (Figure 4). are not present in all infected cats, particularly early in can often be found via a complete blood the disease course.1,3,8–10 In fact, piroplasms may be cell count, although and neutropenia absent in up to 50% of cases at the initial illness7 but can be inconsistent.8,9,22 Anemia is typically normocytic, may persist indefinitely in cats that have recovered from normochromic, and nonregenerative because of the infection.10 Infected macrophages on the feathered edge acute nature of the illness.22 Moderate to marked of a peripheral blood smear may also be visualized and thrombocytopenia is believed to be related to consump-

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diagnosing C. felis infection, but splenomegaly and hepatomegaly would be expected.4,7,8 For cats in which piroplasms have not been identified, samples from fine- needle aspiration of the lymph nodes, spleen, or liver may provide evidence of infection. These organs are typically heavily infiltrated with schizont-loaded macrophages, and infected cells may be readily identifiable by cytologic examination8,22 (Figure 4). Although polymerase chain reaction testing can be used in a research setting to con- firm the presence of C. felis DNA, such testing is not commercially available. Likewise, serologic testing for antibodies to C. felis is neither available nor practical because of the acute nature of the disease process.

Figure 4. Wright’s-stained macrophage with late forms of TREATMENT the C. felis schizont phase and well-developed merozoites. Because there are no proven effective therapies for (Original magnification ×100; courtesy of Dr.Marlyn Whitney, this infection, preventing the disease should be the goal University of Missouri Veterinary Medical Diagnostic Laboratory) of veterinarians and owners. Transmission occurs via a bite from an infected tick, so indoor cats are less likely to be infected than are cats that go outdoors. Ectopara- tive processes, including disseminated intravascular site control is the ideal for all cats. Our preference for coagulation (DIC).8,9,22 Of seven experimentally infected feline tick prevention is topical spray or spot-on fipronil. cats, only one developed a prolonged activated partial Although C. felis infection has been traditionally thromboplastin time (aPTT).22 Coagulation studies viewed as uniformly fatal, there have been recent reports have been reported from relatively few clinical cases but of cats that survive,9,10,24 including those treated with have often identified prolonged aPTT.8,9 In our clinical supportive care alone and in combination with antimi- experience, prolonged aPTT is common and often pro- crobial therapy. Regardless of antimicrobial treatment, found. Erythrophagocytosis has been identified occa- supportive care is crucial for these gravely ill cats. sionally, with hemolysis occurring principally in the Although there is no evidence-based medicine regard-

There are no proven therapies with efficacy against C. felis infection. extravascular compartment.22 Bone marrow crowded ing ideal supportive care, many therapies have been dis- with schizont-laden macrophages may lead to neutrope- cussed and used. Crystalloid fluid therapy is essential to nia, but neutrophilia resulting from an inflammatory preserve intravascular volume, correct dehydration, and response to infection may be identified alternatively.23 maintain tissue perfusion despite DIC.8–10,24 The type of Hyperbilirubinemia is very common as a result of fluid should be chosen based on the individual cat’s both intrahepatic infiltration of schizont-loaded electrolyte status. Because cytauxzoonosis is accompa- macrophages as well as hemolysis,8,9 and liver enzymes nied by hemolysis, enhancing the oxygen-carrying can often be increased. Prerenal azotemia, hyper- capacity of the blood is often required. Options include glycemia, and electrolyte and acid–base disturbances transfusing whole blood, packed erythrocytes, or hemo- have been documented in many infected cats.8,9 Biliru- globin-based oxygen-carrying solutions (e.g., Oxyglo- binuria is common, but hemoglobinuria has not been bin, Biopure Corporation).9,25 A fresh whole blood observed because hemolysis is largely extravascular.22 transfusion provides plasma constituents that may prove Additional diagnostic tests may be considered in ill useful in treating DIC, whereas Oxyglobin provides the cats. Imaging techniques do not contribute directly in most oncotic support. Because DIC is a common com-

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plication of cytauxzoonosis, heparin therapy (100 to 150 lacks efficacy in treating experimentally induced cytaux- U/kg SC q8h) has been recommended prophylactically.9 .10 In addition, the first published case report of a If used to treat established DIC, the dose should be naturally infected domestic cat that survived did not titrated to effect based on measured increases in partial involve administering an antiprotozoal.24 thromboplastin time and should be accompanied by transfusion of fresh or fresh-frozen plasma. Although UNANSWERED QUESTIONS antimicrobials designed to combat bacterial infections A better understanding of why some domestic cats are not useful in eradicating C. felis infection, most survive infection may enhance our ability to prevent or reports of cats that survive describe adjunctive use of treat this infectious disease. Innate resistance may occur such drugs. A variety of antibiotics have been used in some cats, perhaps as a result of limited schizogony. empirically, including sodium ampicillin,8 enrofloxa- In rare instances, domestic cats have been identified cin,9,24 and doxycycline.8 with chronic erythroparasitemia but no known history Definitive treatment options involve antiprotozoals. of clinical illness, similar to the bobcat reservoir.10 The Thus far, prospective studies have failed to demonstrate possibility that these parasitized cats were infected with

Using tick preventatives is the best approach to prevent C. felis infection. efficacy for such therapy. The antiprotozoal hydroxy- a morphologically similar but distinct organism was dis- naphoquinolones parvaquone and buparvaquone are the counted based on nucleotide sequencing of specific gene drugs of choice for Theileria infection of African cattle. segments from the organism as well as through antibody Despite the close relationship of C. felis to Theileria spp, detection.3,10 The existence of a less virulent strain of C. these drugs have demonstrated a complete lack of effi- felis seems to be a more likely explanation for at least cacy in treating cytauxzoonosis in trials to date.19 some of the survivors, particularly because many of the Recent publications have described using imidocarb 18 cats that survived as documented by Meinkoth et al10 dipropionate (Imizol, Schering-Plough Animal Health) were from a single geographically limited area. or diminazene aceturate (Ganaseg, Novartis Animal It is still unclear which tick species are capable of Health [not available in the United States]) to treat cy- transmitting infection. Certainly, D. variabilis ticks are tauxzoonosis. These aromatic diamidine compounds are capable vectors for disease transmission.11 However, used to treat various protozoal agents, including Babesia numerous other tick species are also likely to feed on spp and African trypanosomiasis.26,27 Imidocarb is read- wild or domestic cats.13 Furthermore, we have identified ily available in the United States. If imidocarb is used, C. felis DNA in not only D. variabilis but also Ambly- atropine pretreatment should be administered to mini- omma americanum ticks that were collected from regions mize adverse cholinergic effects. In a single anecdotal in which the infection is endemic. No published studies report, five of six cats treated with diminazene aceturate have evaluated the ability of A. americanum or other tick (two doses at 2 mg/kg IM 3 to 7 days apart) and one cat species that feed on cats to serve as competent vectors treated with imidocarb dipropionate (two doses at 2 for transmission. mg/kg IM 7 days apart) survived infection. All cats received simultaneous aggressive supportive care.9 CONCLUSION Although encouraging, anecdotal reports do not pro- Despite the devastating nature of C. felis infection in vide proof of treatment efficacy. Survival may have been domestic cats, the current understanding of feline cytaux- related to supportive care or C. felis strain variation rather zoonosis is incomplete. Presumptive diagnosis in endemic than to antiprotozoal drug therapy. In fact, in a recent regions is often based on nonspecific but compatible his- report of 18 cats that survived infection with C. felis,only torical and physical findings. Definitive diagnosis relies a single cat received treatment with an antiprotozoal (i.e., on identifying the organism on either peripheral blood imidocarb dipropionate). This same report also men- smears or tissue aspirates. Prospective controlled studies tioned unpublished work that suggested that imidocarb should be conducted before a particular treatment can be

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endorsed. This is particularly true when the treatment 22. Franks PT, Harvey JW, Shields RP, et al: Hematological findings in experi- mental feline cytauxzoonosis. 24(4):395–401, 1988. itself carries significant expense or risk of adverse effects. JAAHA 23. Meinkoth JH, Cowell RL, Cowell AK: What’s your diagnosis: Cytauxzoon For now, preventing infection in endemic regions must be felis infection. Vet Clin Pathol 25(2):48, 1996. emphasized. Although no vaccine is available, stringent 24. Walker DB, Cowell RL: Survival of a domestic cat with naturally acquired measures to prevent tick attachment should provide a cytauxzoonosis. JAVMA 206(9):1363–1365, 1995. large measure of protection for at-risk cats. 25. Callan MB, Rentko VT: Clinical application of a hemoglobin-based oxygen-car- rying solution. Vet Clin North Am Small Anim Pract 33(6):1277–1293, 2003. 26. Egbe-Nwiyi TN, Anita RE: The effect of trypanocidal drug treatment on the REFERENCES hematological changes in Trypanosoma brucei brucei infected splenectomized 1. Wagner JE: A fatal cytauxzoonosis-like disease in cats. JAVMA dogs. Vet Parasitol 50(1–2):23–33, 1993. 168(7):585–588, 1976. 27. Penzhorn BL, Lewis BD, de Waal DT, et al: Sterilisation of Babesia canis 2. Kier AB, Wightman SR, Wagner JE: Interspecies transmission of Cytauxzoon infections by imidocarb alone or in combination with diminazene. J S Afr Vet felis. Am J Vet Res 43(1):102–105, 1982. Med Assoc 66(3):157–159, 1995. 3. Cowell RL, Panciera RJ, Fox JC, et al: Feline cytauxzoonosis. Compend Con- tin Educ Pract Vet 10(6):731–735, 1988. 4. Kier AB, Wagner JE, Kinden DA: The pathology of experimental cytaux- ARTICLE #5 CE TEST zoonosis. J Comp Pathol 97(4):415–432, 1987. This article qualifies for 2 contact hours of continuing CE 5. Blouin EF, Kocan AA, Kocan KM, et al: Evidence of a limited schizogonous education credit from the Auburn University College of cycle for Cytauxzoon felis in bobcats following exposure to infected ticks. J Wildl Dis 23(3):499–501, 1987. Veterinary Medicine. Subscribers may purchase individual 6. Simpson CF, Harvey JW, Lawman MJ, et al: Ultrastructure of schizonts in CE tests or sign up for our annual CE program. Those the liver of cats with experimentally induced cytauxzoonosis. Am J Vet Res who wish to apply this credit to fulfill state relicensure 46(2):384–390, 1985. requirements should consult their respective state 7. Ferris DH: A progress report on the status of a new disease of American cats: authorities regarding the applicability of this program. Cytauxzoonosis. Comp Immunol Microbiol Infect Dis 1(4):269–276, 1979. To participate, fill out the test form inserted at the end 8. Hoover JP, Walker DB, Hedges JD: Cytauxzoonosis in cats: Eight cases (1985–1992). JAVMA 205(3):455–460, 1994. of this issue or take CE tests online and get real-time 9. Greene CK, Lattimer K, Hopper E, et al: Administration of diminazene ace- scores at www.CompendiumVet.com. turate or imidocarb dipropionate for treatment of cytauxzoonosis in cats. JAVMA 215(4):497–500, 1999. 1. Which species is believed to be the definitive 10. Meinkoth J, Kocan AA, Whitworth L, et al: Cats surviving natural infection host of C. felis? with Cytauxzoon felis: 18 cases (1997–1998). J Vet Intern Med 14(5):521–525, 2000. a. bobcat d. fox 11. Blouin EF, Kocan AA, Glenn BL, et al: Transmission of Cytauxzoon felis b. coyote e. domestic dog (Kier, 1979) from bobcats, Lynx rufus (Schreber), to domestic cats by Derma- c. domestic cat centor variabilis (Say). J Wildl Dis 20(3):241–242, 1984. 12. Glenn BL, Kocan AA, Blouin EF: Cytauxzoonosis in bobcats. JAVMA 2. Clinical diagnosis of C. felis infection should be 183(11):1155–1158, 1983. based on 13. Akucewich LH, Philman K, Clark A, et al: Prevalence of ectoparasites in a a. positive results from polymerase chain reaction testing. population of feral cats from north central Florida during the summer. Vet Parasitol 109(1–2):129–139, 2002. b. a fourfold increase in antibody titer. 14. Garner MM, Lung NP, Citino S, et al: Fatal cytauxzoonosis in a captive- c. identification of piroplasms in erythrocytes. reared white tiger (Panthera tigris). Vet Pathol 33(1):82–86, 1996. d. identification of schizonts in mononuclear cells. 15. Rotstein DS, Taylor SK, Harvey JW, et al: Hematologic effects of cytaux- e. identification of either piroplasms or schizonts. zoonosis in Florida panthers and Texas cougars in Florida. J Wildl Dis 35(3):613–617, 1999. 3. Prominent clinical findings in cats infected with 16. Zinkl JG, McDonald SE, Kier AB, et al: Cytauxzoon-like organisms in ery- C. felis would not include throcytes of two cheetahs. JAVMA 179(11):1261–1262, 1981. a. pyrexia. d. uveitis. 17. Kier AB, Greene CE: Cytauxzoonosis, in Greene CE (ed): Infectious Diseases b. icterus. e. pallor. of the Dog and Cat. Philadelphia, WB Saunders, 1998, pp 470–473. c. splenomegaly. 18. Wagner JE, Ferris DH, Kier AB, et al: Experimentally induced cytauxzoono- sis-like disease in domestic cats. Vet Parasitol 6(4):305–311, 1980. 19. Motzel SL, Wagner JE: Treatment of experimentally induced cytauxzoonosis 4. Which statement regarding piroplasms of C. felis in cats with parvaquone and buparvaquone. Vet Parasitol 35(1–2):131–138, is incorrect? 1990. a. Piroplasms are not always identifiable at the onset of 20. Glenn BL, Stair EL: Cytauxzoonosis in domestic cats: Report of two cases in clinical illness with cytauxzoonosis. Oklahoma, with a review and discussion of the disease. JAVMA 184(7):822–824, 1984. b. Cats that have recovered from infection may con- 21. Wightman SR, Kier AB, Wagner JE: Feline cytauxzoonosis: Clinical features tinue to have low numbers of identifiable piroplasms of a newly described blood parasite disease. Feline Pract 7(3):23–26, 1977. indefinitely.

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c. The severity of clinical illness is well correlated with 7. Which laboratory change would not be expected the number or piroplasms in circulating blood cells. in a cat with cytauxzoonosis? d. Piroplasms are simply merozoites that have been a. normocytic anemia d. thrombocytopenia taken up by erythrocytes via endocytosis. b. hemoglobinuria e. elevated liver enzymes e. Signet ring, “safety pin,” and tetrad forms as well as c. bilirubinemia chains of organisms resembling cocci are all possible morphologies for piroplasms. 8. C. felis infection in domestic cats has not been reported in a. California. d. Tennessee. 5. Prospective studies have documented the effi- b. Oklahoma. e. Arkansas. cacy of ______in treating C. felis infection. c. Georgia. a. imidocarb dipropionate d. enrofloxacin b. diminazene aceturate e. none of the above 9. Cytauxzoonosis is best prevented by c. parvaquone a. routine serologic screening for early infection. b. careful screening of all potential blood donors. 6. Which statement regarding disease transmission c. strict isolation and quarantine of infected cats. is correct? d. population control of feral cats that might serve as a. Close contact with cats infected with C. felis poses a disease reservoirs. zoonotic risk to immunosuppressed humans. e. preventing tick attachment. b. D. variabilis is a proven competent vector for trans- mission of C. felis to cats. 10. Which complication is most likely to be associ- c. Mutual grooming and mating can spread C. felis infec- ated with feline cytauxzoonosis? tion between domestic cats. a. acute renal failure d. Immunosuppressed mice can be infected and used as b. severe gastrointestinal ulceration a model to study C. felis in cats. c. disseminated intravascular coagulation e. Transfusion of piroplasm-containing erythrocytes d. peripheral neuropathy induces clinical illness in recipient cats. e. rhabdomyolysis

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