Michael R. Lappin,     Fort Collins, Colorado

Agent and Epidemiology

T. gondii is one of the most prevalent parasites infecting warm-blooded vertebrates; one survey of clinically ill cats in the United States showed an overall seroprevalence rate of 31.6% (Vollaire, Radecki, and Lappin, 2005). Approximately 20% of dogs in the United States are seropositive for T. gondii antibodies. Only cats complete the coccidian life cycle and pass environmentally resistant oocysts in feces. Dogs do not produce T. gondii oocysts like cats but can transmit oocysts mechanically after ingesting feline feces. Sporozoites develop in oocysts after 1 to 5 days of exposure to oxygen and appropriate environmental temperature and humidity. Thus, to lessen the potential of exposure to T. gondii for veterinary staff members in the laboratory, fresh feces should be used for fecal flotation, or the feces should be stored refrigerated until examined. Tachyzoites are the rapidly dividing stage of the organism; they disseminate in blood or lymph during active infection and replicate rapidly intracellularly until the cell is destroyed. Tachyzoites can be detected in blood, aspirates, and effusions in some dogs or cats with disseminated disease. Bradyzoites are the slowly dividing, persistent tissue stage that form in the extraintestinal tissues of infected hosts as immune responses attenuate tachyzoite replication. Bradyzoites form readily in the central nervous system (CNS), muscles, and visceral organs. T. gondii bradyzoites can be the source of reactivated acute infection (e.g., during immune suppression by feline immunodeficiency virus [FIV] or high-dose cyclosporine therapy), or they may be associated with some chronic disease manifestations (e.g., uveitis). Infection of warm-blooded vertebrates occurs after ingestion of any of these three life stages of the organism or transplacentally. In addition, it appears that cats can be infected lactationally, dogs can be infected by venereal contact, and repeated infections can occur in seropositive animals. Cats infected by ingesting T. gondii bradyzoites during carnivorous feeding shed oocysts in feces from 3 to 21 days. Fewer numbers of oocysts are shed for longer time periods if sporulated oocysts are ingested. Sporulated oocysts can survive in the environment for months to years and are resistant to most disinfectants. For dogs, cats, and humans it is believed that bradyzoites persist in tissues for the life of the host, regardless of whether drugs with presumed T. gondii activity are administered. Thus serum antibody titers are unlikely to decrease after treatment.

Clinical Features of Feline Infection

Approximately 10% to 20% of cats inoculated experimentally with T. gondii tissue cysts develop self-limiting small bowel diarrhea for 1 to 2 weeks; local replication of the organism during the intestinal phase of infection is presumed the cause. However, detection of T. gondii oocysts in feces rarely is reported in studies of client-owned cats with diarrhea, in part because of the short oocyst shedding period. Although T. gondii enteroepithelial stages were found in intestinal tissues from two cats with inflammatory bowel disease that responded to anti–T. gondii drugs, in the author’s experience chronic gastrointestinal disease in cats from toxoplasmosis is uncommon.

Fatal toxoplasmosis can develop during acute dissemination and intracellular replication of tachyzoites; hepatic, pulmonary, CNS, and pancreatic tissues commonly are involved (Dubey et al, 2009). Transplacentally or lactationally infected kittens develop the most severe signs of extraintestinal toxoplasmosis and generally die of pulmonary or hepatic disease. Common clinical findings in cats with disseminated toxoplasmosis include depression, anorexia, fever followed by hypothermia, peritoneal effusion, icterus, and dyspnea. If a host with chronic toxoplasmosis is immunosuppressed, bradyzoites in tissue cysts can replicate rapidly and disseminate again as tachyzoites; this is common in humans with acquired immune deficiency syndrome (AIDS). Disseminated toxoplasmosis has been documented in cats concurrently infected with feline leukemia virus (FeLV), FIV, and feline infectious peritonitis virus. Commonly used clinical doses of glucocorticoids do not appear to predispose to activated toxoplasmosis. However, administration of cyclosporine to cats or dogs with renal transplantations or dermatologic disease has been associated with fatal disseminated toxoplasmosis (Barrs, Martin, and Beatty, 2006; Bernstein et al, 1999). Cats started on cyclosporine before exposure to T. gondii are most likely to develop significant illness, particularly if the trough blood level is higher than the normal range. Administration of cyclosporine at 7.5 mg/kg PO daily for 42 days failed to reactivate T. gondii in one experimental model performed by the author.

Chronic toxoplasmosis with vague and recurrent clinical signs of disease apparently occurs in some cats. T. gondii infection should be on the differential diagnoses list for cats with anterior or posterior uveitis, fever, muscle hyperesthesia, weight loss, anorexia, seizures, ataxia, icterus, diarrhea, or pancreatitis.

Based on results of T. gondii–specific aqueous humor antibody and polymerase chain reaction (PCR) studies, toxoplasmosis appears to be one of the most common infectious causes of uveitis in cats. It is unknown why the majority of cats infected with T. gondii are affected subclinically and other cats develop clinical signs of disease. Similar to what is reported in humans, kittens infected with T. gondii transplacentally or lactationally commonly develop ocular disease. Immune complex formation and deposition in tissues and delayed hypersensitivity reactions may be involved in chronic clinical toxoplasmosis. Because none of the anti-Toxoplasma drugs totally clear the body of the organism, recurrence of disease is common. This fact should be made clear to owners in discharge instructions, and the communication noted in the medical record.

Clinical Features of Canine Infection

Before 1988 many dogs diagnosed with toxoplasmosis based on histologic evaluation truly were infected with Neospora caninum. However, T. gondii infection frequently occurs in dogs and rarely can be associated with clinical disease. The most common syndromes associated with disseminated toxoplasmosis in dogs have involved the respiratory, gastrointestinal, or neuromuscular systems, resulting in fever, vomiting, diarrhea, dyspnea, and icterus. Disseminated toxoplasmosis is most common in immunosuppressed dogs, such as those with canine distemper virus infection or those receiving cyclosporine to prevent rejection of a renal transplant.

Neurologic signs depend on the location of the primary lesions and include ataxia, seizures, tremors, cranial nerve deficits, paresis, and paralysis. Dogs with myositis exhibit weakness, stiff gait, or muscle wasting. Rapid progression to tetraparesis and paralysis with lower motor neuron dysfunction can occur. Myocardial infection resulting in ventricular arrhythmias occurs in some infected dogs. Retinitis, anterior uveitis, iridocyclitis, nodular conjunctivitis, and optic neuritis occur in some dogs with toxoplasmosis but for unknown reasons seem to be less common than in the cat.

Clinical Diagnosis

Cats and dogs with clinical toxoplasmosis can have a variety of clinicopathologic and radiographic abnormalities, but none of the findings alone can be used to document the disease. Nonregenerative anemia, neutrophilic leukocytosis, lymphocytosis, monocytosis, neutropenia, eosinophilia, proteinuria, bilirubinuria, and increases in serum globulins and bilirubin concentration can be seen. In addition, increased activities of creatine kinase, alanine aminotransferase, alkaline phosphatase, and lipase occur in some affected animals. Pulmonary toxoplasmosis most commonly causes diffuse interstitial-to-patchy alveolar patterns or pleural effusion. Cerebrospinal fluid (CSF) protein concentrations and cell counts are often higher than normal; the predominant white blood cells in CSF are small mononuclear cells and neutrophils. The detection of these abnormalities should direct the clinician to perform additional, more specific T. gondii tests, particularly if in cases of a high likelihood of exposure to sporulated oocysts or uncooked meat or historical or other evidence of immunodeficiency.

The antemortem definitive diagnosis of toxoplasmosis can be made if the organism or its DNA is demonstrated; this is most likely to be achieved in cats or dogs with acute disseminated disease. Tachyzoites or bradyzoites have been detected in tissues, effusions, bronchoalveolar lavage fluids, aqueous humor, or CSF. Detection of T. gondii organisms is unlikely in cats or dogs with chronic disease manifestations. T. gondii DNA can be amplified from tissues and fluids; thus PCR detection is considered more sensitive and specific than cytologic or histopathologic detection of the organism. Multiple laboratories offer PCR assays that can amplify DNA of T. gondii and N. caninum (dogs); these assays should be considered if T. gondii or N. caninum is suspected but is not documented cytologically. Tissues, fluids, or aspirates for T. gondii PCR testing can be maintained frozen until assayed because the DNA is stable. T. gondii PCR assays seem to be less sensitive if performed on formalin-fixed samples; thus use of fresh tissue is preferred. Immunohistochemistry also can be performed on tissues to document the presence of T. gondii and to differentiate T. gondii from N. caninum.

Detection of 10 × 12 µm diameter oocysts in feces in cats with diarrhea suggests toxoplasmosis but is not definitive because Besnoitia and Hammondia spp. infections of cats produce morphologically similar oocysts. In these cases T. gondii serology should be performed, and, if the primary infection is T. gondii, seroconversion should be documented within 2 to 3 weeks. In dogs N. caninum oocysts are morphologically similar to T. gondii oocysts. These dogs can be screened for N. caninum and T. gondii antibodies in 2 to 3 weeks to determine the organism that was associated with the infection. Alternately, results of T. gondii and N. caninum PCR assays can be used to differentiate if a sample containing microbial DNA is available.

T. gondii antibodies can be detected in serum by a variety of different methods. Serum antibody assay results can be positive in healthy animals as well as those with clinical signs of toxoplasmosis; thus to make an antemortem diagnosis of clinical toxoplasmosis is impossible based on results of these tests alone. Of the serum tests, IgM titers correlate best with clinical toxoplasmosis because this antibody class is detected rarely in serum of healthy animals; thus many laboratories offer IgM and IgG test results separately. The antemortem diagnosis of clinical toxoplasmosis can be based tentatively on the combination of (1) clinical signs of disease referable to toxoplasmosis; (2) demonstration of antibodies in serum, which documents exposure to T. gondii; (3) demonstration of an IgM titer of more than 1 : 64 or a fourfold or greater increase in IgG titer, which suggests recent or active infection; (4) exclusion of other common causes of the clinical syndrome; and (5) positive response to appropriate treatment. In dogs neosporosis and toxoplasmosis appear clinically similar; thus the author frequently combines T. gondii and N. caninum serologic tests in his diagnostic workup of suspect patients.

T. gondii antigens or DNA can be detected in the blood of healthy or clinically ill cats and dogs; the source of the organism is likely bradyzoites from tissue cysts (Lee et al, 2008). The combination of T. gondii–specific antibody detection in aqueous humor or CSF and organism DNA amplification by PCR is the most accurate way to diagnose ocular or CNS toxoplasmosis in cats (Powell et al, 2010). CNS toxoplasmosis and neosporosis can appear clinically similar in dogs; thus the author frequently combines PCR testing for both organisms on CSF samples from dogs with inflammatory CNS disease.