Cytauxzoonosis

Edited November 2, 2015

 

 

The Cytauxozoonosis guidelines were first published in the Journal of Feline Medicine and Surgery (2015) 17:637–641 by Albert Lloret et al.; the present update has been authorised by Karin Möstl.

 

 

Synopsis

 

Cytauxzoonosis has been reported worldwide, both in domestic and wild cat species. The parasite is transmitted via ticks, and prevalence is higher in cats with outdoor access and in feral cats.

 

In the US, cytauxzoonosis is typically an acute or peracute, severe febrile disease. Non-regenerative haemolytic anaemia is often present, as are neurological signs, followed by death in nearly all cases.

 

Cats infected with Cytauxzoon spp have been reported in Southern Europe, but clinical signs were mild (and possibly unrelated to the infection).

 

In practice, diagnosis is often obtained from blood smears and/or fine needle aspirates from the liver, spleen and lymph nodes stained with quick Romanowsky-type stains.

 

PCR assays have been developed to confirm the presence of C felis and C ssp but are not useful for a quick diagnosis in practice.

 

Current treatment of choice is a combination of atovaquone (15 mg/kg PO q8h) and azithromycin (10 mg/kg PO q 24h), as well as fluids, heparin and supportive care.

 

Surviving cats may become chronic carriers.

 

Prevention is based on living indoor or use of effective tick treatment in outdoor cats.

 

 

 

Agent properties

 

Cytauxzoon species are apicomplexan hemoparasites (family Theileriidae) of wild and domestic cats transmitted by ticks. C felis is the main species, with numerous strains or genotypes2,3 producing infection and severe disease in domestic cats, lions and tigers. Wild cats (bobcats, mountain lions, ocelots, spotted cats and jaguars) in North and South America can act as reservoir or incidental hosts. Domestic cats may also present subclinical infections and also act as reservoirs.4,5 In some endemic areas, the prevalence of subclinical infection in cats may be as high as 30 %.6 Tick vectors for C felis are Amblyomma americanum and Dermacentor variabilis ticks.7,8,9

 

Other cytauxzoon species have been identified: C manul in Pallas cats (Mongolia), C sp in Iberian Lynx and domestic cats in Spain10 and in domestic cats in Italy.11 The tick vectors for the European species are unknown, but are most likely  Dermacentor sp or Ixodes ricinus.

 

 

Epidemiology

 

Cytauxzoonosis has been documented in wild felids as Bobcats, Florida panthers and Texas cougars. The first cases in domestic cats were documented in 1976.1 For many years, cytauxzoonosis in domestic cats was only reported in North America (South eastern and central states and mid-Atlantic regions) and South America; in recent years the infection has also been documented in Europe.

 

It has been hypothesized that infection in domestic cats was the result of a host species jump from bobcats, where the infection prevalence may be high.8

 

The disease shows a seasonal incidence from spring to early fall,12,13 associated with peak activity of the tick vectors. There is a significant association between infection and outdoor access, and with feral cats in areas where vector ticks are prevalent.12 No association with gender, breed, age and retroviral status has been found.11

 

A hyperendemic focus may be found within endemic areas, but is likely due to tick exposure of cats rather than to cat-to-cat transmission, which has never been proven.14,15 In some areas in the USA, cytauxzoonosis has been increasingly diagnosed in the last decade, and is considered an emerging disease.13

 

In recent years, the infection has also been documented in Europe. Cases have been reported from France19 and the south of Spain, in Iberian Lynx10,16,17 and domestic cats.18 Moreover, a case series was reported in northeastern Italy (Trieste) and two cases in central Italy.11,20 In the Trieste region, samples from domestic and feral cats showed a 23 % prevalence of infection, with a 30% prevalence in feral cats. The Cytauxzoon species in the European cases are different from C felis, the cause of infection and disease in the USA.

 

 

Pathogenesis

 

The life cycle and complex pathogenesis has been well described for this infection.21 Vector ticks ingest merozoite-infected red blood cells from the natural reservoir host (bobcat, lynx or domestic cats). The parasite initiates a process of sexual replication (gametogenesis) in the tick gut and salivary glands. This leads to the formation of sporozoites, which are the infective form and can be transmitted if the tick attaches to a domestic cat. Sporozoites infect endotelial-associated mononuclear cells and undergo asexual replication within the macrophages that become a large structure known as schizonts – large enough to occlude blood vessels, especially in the liver, spleen and lungs. Widespread dissemination of schizonts results in parasitic thrombosis, circulatory impairment, tissue infection and severe systemic inflammatory response, which can lead to multi-organ dysfunction and failure and death within 3 weeks after infection.22 When schizonts rupture in the circulation, large numbers of merozoites are released infecting red blood cells and additional mononuclear cells. This is the late-stage with erythroparasitaemia (piroplasma structures within red blood cells) which can be readily observed in blood smears and may lead to haemolytic anaemia and erythrophagocytosis.

 

Recent studies have evaluated systemic and lung immune responses in cats naturally infected with C felis based on serum concentrations of TNFα, IL-1 β and serum proteins, immunohistochemistry expression of several inflammatory mediators and PCR assay for CD18. Both studies show a marked systemic and lung pro-inflammatory response that can contribute to the pathogenesis of the disease and is even higher in cats that died compared with survivors.23,24

 

 

Clinical presentation

 

Cytauxzoonosis (C felis) in the USA is typically an acute or peracute severe febrile disease. Clinical signs are nonspecific and consist of depression, anorexia, high fever, icterus, dyspnoea, tachycardia, generalized pain and vocalization. Signs of haemolytic anaemia are frequent (pale mucosa membranes, pigmenturia, splenomegaly, hepatomegaly). Some cats may present or evolve to late stages with neurological signs (ataxia, seizures, nystagmus), hypothermia, moribund state and coma. Many cats die within one week after the onset of clinical signs.14,25 Veterinarians practicing in an endemic area must suspect of cytauxzoonosis in front of any cat with an acute severe disease.

 

Frequent clinicopathological signs include non-regenerative anaemia, leukopenia with toxic changes, thrombocytopenia, hyperbilirubinaemia, bilirubinuria and an increase of liver enzymes. These changes are associated to erythrophagocytosis and systemic inflammatory response syndrome (SIRS). Coagulation times usually are prolonged due to disseminated intravascular coagulation (DIC). Other biochemical abnormalities are hypoalbuminaemia, hyperglycaemia, pre-renal azotaemia and electrolyte and acid-base disturbances associated to the SIRS state.14,25

 

Diagnostic imaging reveals nonspecific signs consisting in hepatosplenomegaly in abdominal radiographs and/or ultrasound and a pulmonary interstitial-alveolar pattern in thorax radiographs.

 

Cytauxzoon sp infection reported in European cats (Italy, Spain, France) is probably less virulent than C felis infection as the majority of cats were healthy showing only low-level erythroparasitaemia (merozoites within red blood cells) as an incidental finding. In some cats, anaemia was found and one cat died after a short course of a severe disease, but no schizont structures were found in tissues, so cytauxzoonosis was not confirmed.

 

 

Diagnosis

 

In clinical practice, diagnosis is usually obtained by identification of C felis in blood smears and/or fine needle aspirates from the liver, spleen and lymph nodes stained with quick Romanowsky-type stains used in practice.

 

Fig. 1. Three C felis piroplasms within erythrocytes on a feline blood smear.

Fig. 1. Three C felis piroplasms within erythrocytes on a feline blood smear. Courtesy The Merck Veterinary Manual, Dr. Jaime L. Tarigo

 

Observation of schizont-infected myeloid cells on blood and/or tissue smears is the diagnostic test of choice because confirms acute disease. They are seen as very large (50-250 µm diameter), single cells with an eccentric nucleus containing a single prominent nucleus. The cytoplasm contains variable amounts (few to thousands) basophilic particles, which are developing merozoites. These cells may be confused with platelet clumps. The sensitivity of blood smears may be low, so fine needle aspirates and cytology of liver, spleen, lymph nodes and lungs are indicated if blood smears are not diagnostic in a suspected case.

 

Fig. 2. C felis schizonts A) on the feathered edge of a feline blood smear and B) in a touch imprint of a peripheral lymph node from a cat with acute cytauxzoonosis. From the Merck Veterinary Manual, with permission.

Fig. 2. C felis schizonts A) on the feathered edge of a feline blood smear and B) in a touch imprint of a peripheral lymph node from a cat with acute cytauxzoonosis. From the Merck Veterinary Manual, with permission.

 

Observation of merozoits (piroplasms) within red blood cells in thin blood smears stained with Romanowsky-type stains is supportive, but does not always confirm acute disease. Piroplasms are round to oval structures 1 to 2 µm in diameter with a dark purple eccentric nucleus within a pale light blue cytoplasm (signet ring shaped), but in some cases may be more elongated with a bipolar nucleus. One to four merozoits within red blood cells may be observed. Sensitivity is not very good, as merozoits appear late in the course of the disease, so they can be absent or in very low numbers in probably more than 50 % of the cats with acute disease. Blood smears should be done every day because they can appear over the course of the disease. Distal edges of the blood smears are the best place to look for them. Moreover, observation of merozoits does not confirm acute disease, and can be an incidental finding in healthy cats, in cats that survived acute infection or in cats with clinical signs due to another disease.

 

PCR assays have been developed to confirm the presence of C felis and C sp,10,11,14 but so far they are not useful for a quick diagnosis in practice. It is recommended tough that samples from suspected cats should be submitted to specific laboratories to further confirm the infection. Low levels of parasitaemia can only be detected by PCR assays.5 In one clinical trial, parasitaemia was determined by qPCR and was significantly lower in surviving cats versus nonsurviving, so qPCR results might be of prognostic value.26

 

 

Treatment

 

Historically, cytauxzoonosis has been considered a fatal disease with mortality nearly to 100 %. With the recent advances on treatment and/or differences in strains pathogenicity, this is no longer true, although the prognosis remains guarded.27,28

 

Supportive and critical care treatment (intensive fluid and oxygen therapy, anti-thrombus formation drugs like unfractionated heparin 200 U/kg SC q8h, blood products, antibiotics, analgesics) are extremely important to keep the cat alive while the antiprotozoal drugs and immune system do their work. Many cats get worse during the first days and often die, but if they survive, a gradual improvement is seen over the next days.26

 

Some antiprotozoal drugs have been reported in case reports or experimental studies (diminazene, imidocarb dipropionate, sodium thiacetarsamide, tetracycline, parvaquone or buparvaquone) but efficacy has not been proven.27,28,29

 

Imidocarb has been the drug of choice for many years, although it was not known if it provided any advantage over supportive care alone. However, an open-label randomized prospective clinical trial demonstrated better survival rates (60 % versus 26 %) with the combination of atovaquone (15 mg/kg PO q8h) and azithromycin (10 mg/kg PO q 24h) compared to imidocarb (3.5 mg/kg IM once) in 80 cats with acute disease. Mortality was high (41/80 cats). Most cats died during the first 3 days after presentation, only 3 cats dying after the 3rd day of treatment. Supportive treatment was the same in all cats, including fluids, heparin and supportive care. This study suggests that this treatment combination plus supportive treatment are the current treatment of choice.26 In some cats, a naso-oesophageal tube may be needed to administer drugs and enteral feeding.

 

Cats surviving the acute infection may become chronic carriers for life with piroplasms within the red blood cells. These cats act as reservoirs and may transmit the infection through tick vectors.

 

A recent study failed to demonstrate efficacy of diminazene with higher doses (4 mg/kg IM) for 5 consecutive days to eliminate or reduce parasite burden in chronic carrier cats. Moreover, multiple adverse effects appeared, so this treatment is not recommended.30

 

There is no currently vaccine against C felis, although first preliminary studies are being conducted.31

 

Prevention is based on living indoor or use of effective tick treatment in outdoor cats. Efficacy on the prevention of C felis transmission using an acaricide collar (imidacloprid 10 % plus flumethrin 4.5 %) has been proven in a controlled prospective clinical trial. Two groups of cats (cats with and without collar) were exposed to ticks (A americanum) infected with C felis. No cats with collar versus 90 % of the cats with no collar were infected.32

 

Testing for the presence cytauxzoon is advised in feline blood donors. Although inoculation of piroplasms within red blood cells in a blood transfusion does not produce development of schizont structures and disease, cats can become chronic carriers and an infection reservoir.

 

 

Prognosis

 

Prognosis should be considered guarded to fair, if proper intensive care is provided and atovaquone is available, in cytauxzoonosis in the USA. It has been suggested that different C felis strains may vary in pathogenicity to domestic cats having an influence in survival as some cats have survived after no receiving antiprotozoal drugs.2,27,33 Anyway, it is recommended to treat cats in well-equipped hospitals where the best supportive treatment can be provided.

 

Cytauxzoonosis reported in Europe has a good prognosis: so far, only cats with subclinical infection or signs of mild disease (anaemia, diarrhoea), possibly unrelated with the infection, have been documented.11,20

 

 

References

 

1. Wagner JE. A fatal cytauxzoonosis-like disease in cats. J Am Vet Med Assoc 1976; 168(7): 585-588.

2. Brown HM, Berghaus RD, Latimer KS, Britt JO, Rakich PM and Peterson DS. Genetic variability of Cytauxzoon felis from 88 infected domestic cats in Arkansas and Georgia. J Vet Diagn Invest 2009; 21(1): 59-63.

3. Shock BC, Birkenheuer AJ, Patton LL, Olfenbuttel C, Beringer J, Prange S, et al. Variation in the ITS-1 and ITS-2 rRNA genomic regions of Cytauxzoon felis from bobcats and pumas in the eastern United States and comparison with sequences from domestic cats. Vet Parasitol 2012; 190(1-2): 29-35.

4. Haber MD, Tucker MD, Marr HS, Levy JK, Burgess J, Lappin MR, et al. The detection of Cytauxzoon felis in apparently healthy-free-roaming cats in the USA. Vet Parasitol 2007; 146(3-4): 316-320.

5. Brown HM, Latimer KS, Erikson LE, Cashwell ME, Britt JO and Peterson DS. Detection of persistent Cytauxzoon felis infection by polymerase chain reaction in three asymptomatic domestic cats. J Vet Diagn Invest 2008; 20(4): 485-488.

6. Brown HM, Lockhart JM, Latimer KS and Peterson DS. Identification and genetic characterization of Cytauxzoon felis in asymptomatic domestic cats and bobcats. Vet Parasitol 2010; 172(3-4): 311-316.

7. Reichard MV, Edwards AC, Meinkoth JH, Snider TA, Meinkoth KR, Heinz RE, et al. Confirmation of Amblyomma americanum (Acari:Ixodidae) as a vector for Cytauxzoon felis (Piroplasmorida:Theileriidae) to domestic cats. J Med Entomol 2010; 47(5): 890-896.

8. Shock BC, Murphy SM, Patton LL, Shock PM, Olfenbuttel C, Beringer J, et al. Distribution and prevalence of Cytauxzoon felis in bobcats (Lynx rufus), the natural reservoir, and other wild felids in thirteen states. Vet Parasitol 2011; 175(3-4): 325-330.

9. Blouin EF, Kocan AA, Glenn BL, Kocan KM and Hair JA. Transmission of Cytauxzoon felis Kier, 1979 from bobcats, Felis rufus (Schreber), to domestic cats by Dermacentor variabilis (Say). J Wild Dis 1984; 20(3): 241-242.

10. Millán J, Naranjo V, Rodríguez A, de la Lastra JM, Mangold AJ and de la Fuente J. Prevalence of infection and 18S rRNA gene sequence of Cytauxzoon species in Iberian Lynx (Lynx pardinus) in Spain. Parasitology 2007; 134: 995-1001.

11. Carli E, Trotta M, Chinelli R, Drigo M, Sinigoi L, Tosolini P, et al. Cytauxzoon sp infection in the first endemic focus described in domestic cats in Europe. Vet Parasitol 2012; 183: 343-352.

12. Reichard MV, Baum KA, Cadenhead SC and Snider TA. Temporal occurrence and environmental risk factors associated with cytauxzoonosis in domestic cats. Vet Parasitol 2008; 152: 314-320.

13. Miller J and Davis CD. Increasing frequency of feline cytauxzoonosis cases diagnosed in western Kentucky from 2001 to 2011. Vet Parasitol 2013; 198: 205-208.

14. Birkenheuer AJ, Le JA, Valenzisi AM, Tucker MD, Levy MG and Breitschwerdt EB. Cytauxzoon felis infection in cats in the mid-Atlantic states: 34 cases (1998-2004). J Am Vet Med Assoc 2006; 228: 568-571.

15. Woods JP. Feline cytauxzoonosis. In: Bonagura & Twedt (eds). Kirk’s Current Veterinary Therapy XV. 15th ed. St Louis, MO: Elsevier Saunders, 2013, pp e405-408.

16. Luaces I, Aguirre E, García-Montijano M, Velarde J, Tesouro MA, Sánchez C, et al. First report of an intraerythrocytic small piroplasm in wild Iberian lynx (Lynx pardinus). J Wild Dis 2005; 41: 810-815.

17. Millán J, Candela MG, Palomares F, Cubero MJ, Rodríguez A, Barral M, et al. Disease threats to the endangered Iberian lynx (Lynx pardinus). Vet J 2009; 182: 114-124.

18. Criado-Fornelio A, González-del-Rio MA, Buling-Saraña A and Barba-Carretero JC. The “expanding universe” of piroplasms. Vet Parasitol 2004; 119: 337-345.

19. Criado-Fornelio A, Buling A, Pingret JL, Etievant M, Boucraut-Baralon C, Alongi A, et al. Hemoprotozoa of domestic animals in France: prevalence and molecular characterization. Vet Parasitol 2009; 159: 73-76.

20. Carli E, Trotta M, Bianchi E, Furlanello T, Caldin M, Pietrobelli M, et al. Cytauxzoon sp. infection in two free ranging young cats: clinicopathological findings, therapy and follow up. Turkiye Parazitol Derg 2014; 38: 185-189.

21. Kier AB, Wagner JE and Kinden DA. The pathology of experimental cytauxzoonosis. J Comp Pathol 1987; 97: 415-432.

22. Snider TA, Confer AW and Payton ME. Pulmonary histopathology of Cytauxzoon felis infections in the cat. Vet Pathol 2010; 47: 698-702.

23. Frontera-Acevedo K, Balsone NM, Dugan MA, Makemson CR, Sellers LB, Brown HM, et al. Systemic immune responses in Cytauxzoon felis-infected domestic cats. Am J Vet Res 2013; 74: 901-909.

24. Frontera-Acevedo K and Sakamoto K. Local pulmonary immune responses in domestic cats naturally infected with Cytauxzoon felis. Vet Immunol Immunopathol 2015; 163: 1-7.

25. Hoover JP, Walker DB and Hedges JD. Cytauxzoonosis in cats: eight cases (1985-1992). J Am Vet Med Assoc 1994; 205: 455-460.

26. Cohn LA, Birkenheuer AJ, Brunker JD, Ratcliff ER and Craig AW. Efficacy of atavaquone and azithromycin or imidocarb dipropionate in cats with acute cytauxzoonosis. J Vet Intern Med 2011; 25: 55-60.

27. Meinkoth J, Kocan AA, Whitworth L, Murphy G, Fox JC and Woods JP. Cats surviving natural infection with Cytauxzoon felis: 18 cases (1997-1998). J Vet Intern Med 2000; 14: 521-525.

28. Greene CE, Latimer K, Hooper E, Shoeffler G, Lower K and Cullens F. Administration of diminazene aceturate or imidocarb dipropionate for treatment of cytauxzoonosis in cats. J Am Vet Med Assoc 1999; 215: 497-500.

29. Motzel SL and Wagner JE. Treatment of experimentally induced cytauxzoonosis in cats with parvaquone and buparvaquone. Vet Parasitol 1990; 35: 131-138.

30. Lewis KM, Cohn LA, Marr HS and Birkenheuer AJ. Failure of efficacy and adverse effects associated with dose-intense diminazene diaceturate treatment of chronic Cytauxzoon felis infection in five cats. J Feline Med Surg 2014; 16: 157-163.

31. Tarigo JL, Scholl EH, McK Bird D, Brown CC, Cohn LA, Dean GA, et al. A novel candidate vaccine for cytauxzoonosis inferred from comparative apicomplexan genomics. PLoS One 2013; 8(10). doi:10.1371.

32. Reichard MV, Thomas JE, Arther RG, Hostetler JA, Raetzel KL, Meinkoth JH, et al. Efficacy of an imidacloprid 10% / flumethrin 4.5% collar (Seresto, Bayer) for preventing the transmission of Cytauxzoon felis to domestic cats by Amblyomma americanum. Parasitol Res 2013; 112(1): 11-20.

33. Walker DB and Cowell RL. Survival of a domestic cat with naturally acquired cytauxzoonosis. J Am Vet Med Assoc 1995; 206: 1363-1365.

Back to Top