Case series description

Case 1

A 5-month-old intact male domestic shorthair (DSH) cat was evaluated by its veterinarian because of the sudden onset of lethargy and inability to stand. The cat lived outdoors on a rural farm in central Kansas, in a group of 12 cats. Two other cats on the premises were found dead the day prior to presentation. The cat was unvaccinated, and there was no known exposure to toxins or chemicals.

The cat was moribund and hypothermic upon presentation. Results of a complete blood count showed leukopenia (1070 leukocytes/µl; reference interval [RI] 5500–18,500 leukocytes/µl), with marked neutropenia (240 neutrophils/µl; RI 2500–14,000 neutrophils/µl) and lymphopenia (760 lymphocytes/µl; RI 1500–7000 lymphocytes/µl), mild anemia (hematocrit 21.6%; RI 24–45%) and marked thrombocytopenia (1000 platelets/µl; RI 300,000–800,000 platelets/µl). Serum biochemical analysis findings included high serum total bilirubin concentration (4.1 mg/dl; RI 0.1–0.6 mg/dl), high serum phosphorus concentration (14.3 mg/dl; RI 3.4–8.5 mg/dl), hypoglycemia (38 mg/dl; RI 70–150 mg/dl) and high blood urea nitrogen (BUN) concentration (95 mg/dl; RI 10–30 mg/dl). Feline immunodeficiency virus antibody, feline leukemia antigen and parvovirus antigen testing were negative. Hematology, chemistry and viral testing were performed at the primary care veterinary clinic using point-of-care analyzers and test kits; evaluation of a blood smear was not conducted.

Owing to the grave prognosis for survival, humane euthanasia was performed and the cat was submitted to the Kansas State University Veterinary Diagnostic Laboratory (KSU VDL) for gross necropsy. Gross examination revealed fair body condition and mild post-mortem autolysis. The gingiva, mucous membranes and internal fat stores were diffusely pale to light yellow. Episcleral vessel injection was present in both eyes. The lung lobes had multiple, 3–10 mm diameter parenchymal hemorrhages at the pleural and cut surfaces. The spleen and mesenteric lymph nodes were dark red and enlarged. There were no significant gross lesions in other areas of the body.

Histologic evaluation revealed similar abnormalities in all sampled areas. The pulmonary vessels and alveolar capillaries, mesenteric lymph node cortical and medullary vessels and sinuses, splenic red pulp vessels and sinuses, and the blood vessels and vascular spaces within the brain, liver, heart, pancreas, kidneys and gastrointestinal tract contained large macrophages laden with protozoal schizonts. Macrophages were noted to marginate along vascular endothelium or fill vessel lumens. Cells contained either multiple, irregularly round, developing schizonts with many large, vesiculate nuclei or mature schizonts with 1–3 µm round, lightly basophilic uninucleate merozoites.

Microscopic evaluation of the eyes demonstrated macrophages laden with schizonts diffusely distributed throughout the uveal tract and within retinal blood vessels (Figure 1). The vitreous humor was expanded by moderate amounts of hemorrhage (Figure 1a). The ciliary body of the anterior uveal tract was the area most heavily infiltrated by schizont-laden macrophages (Figure 1b, c), but protozoal organisms were identified within macrophages in all areas of the uveal tract. The retina was pathologically detached and subretinal hemorrhage was present (Figure 1d). No other ocular lesions were noted.

Figure 1

Representative photomicrographs of ocular histopathologic findings in a 5-month-old male intact domestic shorthair cat (cat 1). (a) Sub-gross image of the globe, highlighting vitreal hemorrhage (*) associated with a pathologic retinal detachment. (b) Mixed inflammatory infiltrate affecting the ciliary body and ciliary processes (†). (c) Schizont-laden macrophages (inset, arrows) within ciliary body blood vessels. (d) Schizont-laden macrophage within a retinal blood vessel (arrow). Hematoxylin and eosin

CB = ciliary body; CP = ciliary processes; INL = inner nuclear layer of the retina; ONL = outer nuclear layer of the retina; S = sclera

Gross and microscopic findings were characteristic of cytauxzoonosis due to Cytauxzoon felis infection. Infection was additionally confirmed by identifying C felis schizonts within macrophages from splenic impression smears.

Discussion

Cytauxzoon felis is a hemoprotozoan parasite transmitted by the bite of an infected tick. Recognized vectors are the American dog tick (Dermacentor variabilis) and the lone star tick (Amblyomma americanum).^1–3 Bobcats (Lynx rufus) are the natural reservoir host; the infection is thought to be self-limiting in this species, with affected animals developing a carrier state after recovery.^4,5 C felis is an important emerging infectious disease of domestic cats in the USA owing to the severe, often fatal, illness that develops after infection.^2,6 The disease has not been reported outside wild and domestic felids. The life cycle of C felis is complex, and two distinct tissue forms exist: an erythrocyte phase, called a piroplasm, and a tissue phase within macrophages, called a schizont.⁷ The schizont phase is responsible for clinical disease, beginning approximately 2 weeks after a bite from an infected tick.^1,8 Parasite-laden macrophages rapidly cause partial or total occlusion of blood vessels, leading to vascular obstruction and organ failure.^9,10

To our knowledge, this is the first report of cytaux zoonosis with ocular involvement. From the late 1970s, there have been several case series and single case reports of the disease;^6,9,11–15 however, descriptions of clinically or histologically confirmed ocular lesions do not exist. Reported ophthalmic clinical signs are limited, and generally attributable to non-specific signs of malaise, such as elevated nictitating membranes.^16,17 Conjunctival hyperemia and episcleral vessel injection have been reported in one cat.¹⁷ Likewise, in our report, cat 1 was noted to have episcleral vessel injection on gross post-mortem examination. Our report is the first to describe schizonts identified within the blood vessels of the uveal tract and retina. Though clinical ophthalmic examination was not possible in these cases, the histologic presence of vitreal hemorrhage, subretinal hemorrhage and retinal detachment indicates that abnormalities would be readily observable with an examination of the ocular fundus.

Given the highly vascular nature of the uveal tract, ocular involvement in cytauxzoonosis is not surprising. Extrapolating from clinical observations in other parts of the body, we speculate that a constellation of clinical signs referable to the anemia, thrombocytopenia and disseminated intravascular coagulation that occur in affected cats would develop in the uveal tract.^9,12 Specific ocular clinical signs associated with hemorrhagic diathesis due to microvascular obstruction (hemorrhagic panuveitis) would be expected, including hyphema, hemorrhages within the iris stroma, vitreal hemorrhages (histologically identified in this report) and retinal hemorrhages. Hemorrhage of the choroid or subretinal effusion of fluid due to hypoproteinemia could lead to retinal detachment, which was also identified in this report. These examples of ocular lesions can be present in tick-borne infections of dogs, where diseases such as monocytic ehrlichiosis cause uveitis with intraocular hemorrhage due to coagulopathy, vasculitis or both.^18,19 Vascular obstruction characteristic of the schizont phase of C felis would likely lead to retinal and choroidal ischemia, causing irreversible damage to the neurosensory retina. It is expected that, as in other causes of infectious uveitis, individual cats would exhibit ocular clinical signs of varying magnitude. Cats with cytauxzoonosis can be presented in a significantly obtunded state or experience acute death; therefore, thorough ophthalmic examination may be overlooked or impossible as efforts are focused on supportive therapy. This may explain why no reports of ocular involvement in cytauxzoonosis exist to date; significant ocular clinical signs and blindness may not be easily recognized in a cat with altered mentation and other neurologic deficits. In addition, the time frame and severity of invasion of parasitized macrophages in the uvea is unknown. This may be relevant to the appearance of ocular lesions in affected cats. Future efforts should focus on identifying affected cats and performing complete ophthalmic examinations, so that ante-mortem confirmation of our hypotheses on the ocular lesions of cytauxzoonosis may be confirmed.

Historically, the survival rate for cats infected with C felis has been very low, with mortality approaching 100%. In the largest retrospective study of 34 naturally infected cats, the mortality rate was 94%; 32 cats died or were euthanized owing to rapid clinical deterioration.⁹ Despite the guarded prognosis in cases of cytauxzoonosis, there are reports of survivors, as well as asymptomatic carriers.^{13,15,20–22} Efforts are being made to investigate antiprotozoal treatment options to increase survival rates.^16,23–25 One study reported a successful outcome in five cats treated with diminazene aceturate, an antiprotozoal veterinary drug used for the treatment of babesiosis and trypanosomiasis.²³ The drug was used in conjunction with intensive supportive care and anticoagulant therapy to prevent disseminated intravascular coagulation in that report. In a more recent prospective study, cats treated with a combination of atovaquone and azithromycin were more likely to survive to discharge when compared with cats treated with imidocarb.¹⁶ Sixty percent of cats (n = 32/53) receiving the combination protocol survived, while only 26% of cats (n = 7/27) receiving imidocarb survived. However, overall mortality rate remained high at approximately 51% (41/80), and other factors, including estimated parasitemia, were considered impactful to prognosis.¹⁶

Identifying differences in C felis strain pathogenicity and developing tests to identify various strains,^{20,21,26–28} or vaccines against the protozoan,²⁹ may likewise influence survival. This highlights the importance of documenting the presence of ocular involvement in affected cats. Because of the complications (eg, blindness, glaucoma, phthisis bulbi) that may be associated with ocular clinical signs of cytauxzoonosis, symptomatic treatment of active uveitis is warranted to increase the quality of life for surviving cats.

Conclusions

This is the first description of cytauxzoonosis affecting the eyes in three infected cats. Based on the known clinical course of disease in other organ systems, the ocular histologic findings in these cases and the well recognized ophthalmic clinical signs present with other tick-borne infectious diseases in small animals, we postulate hemorrhagic panuveitis of varying severity as the most likely clinical presentation in affected cats. Complete ophthalmic examination is warranted in all cases of suspected or confirmed cytauxzoonosis, and C felis should be considered as a differential diagnosis for infectious uveitis, especially when external ocular or intraocular hemorrhage is a feature. Prospective gathering of data from clinical ophthalmic examination of affected cats is necessary to confirm the specific ocular manifestations of cytauxzoonosis.

Despite the high mortality rate with this disease, survival is expected to improve with new antiprotozoal and other treatment developments. Identifying and managing ocular manifestations of cytauxzoonosis is important so that the potentially blinding complications that may be associated with ocular involvement can be minimized.