Toxoplasma gondii is a protozoan parasite that infects most species of warm-blooded animals, including humans. Members of the cat family, Felidae, are the only known definitive hosts for the sexual stages of T. gondii and serve as the main reservoirs of infection. Cats become infected with T. gondii through carnivorism or by ingestion of oocysts. Outdoor cats are much more likely to become infected than domestic cats that are confined indoors. After tissue cysts or oocysts are ingested by the cat, organ isms are released and invade epithelial cells of the cat small intestine, where they undergo an asexual cycle followed by a sexual cycle with the formation of oocysts, which are excreted in the feces. The uninfective oocyst takes 1 to 5 days after excretion to become infective. Cats shed oocysts for 1 to 2 weeks and large numbers may be shed, often more than 100,000 per gram of feces. Oocysts survive in the environment for several months to more than 1 year and are resistant to disinfectants, freezing, and drying. However, they are killed by heating to 70° C for 10 minutes. The life cycle in the cat takes approximately 19 to 48 days after infection with the oocysts but only 3 to 10 days after the ingestion of meat infected with cysts (e.g., a mouse) (Figure 1).
Fig1. Life cycle of Toxoplasma gondii.
GENERAL CHARACTERISTICS
There are three infectious stages of T. gondii: the tachyzoites (in groups or clones), the bradyzoites (in tissue cysts), and the sporozoites (in oocysts from cat feces). Tachyzoites rapidly multiply in any cell of the intermediate host and in epithelial cells of the definitive host (cats). Bradyzoites are found within the tissue cysts and usually multiply very slowly; the cyst may contain few to hundreds of organisms, and intramuscular cysts may reach 100 µm in size. The tissue cysts can be found in visceral organs such as the lungs, liver, and kidneys; however, they are more prevalent in the brain, eyes, and skeletal and cardiac muscle. Intact tissue cysts can persist for the life of the host and do not cause an inflammatory response.
Tachyzoites are crescent-shaped and are 2 to 3 µm wide by 4 to 8 µm long (Table 1). One end tends to be more rounded than the other. Giemsa is the stain of choice; the cytoplasm stains pale blue, and the nucleus stains red and is situated toward the broad end of the organism.
Table1. Morphology of Toxoplasma gondii Stages Found in Humans
Cysts are formed in chronic infections, and the brady zoites within the cyst wall are strongly periodic acid-Schiff positive. During the acute phase, there may be groups of tachyzoites that appear to be cysts; however, they are not strongly periodic acid-Schiff positive and have been termed pseudocysts.
PATHOGENESIS AND SPECTRUM OF DISEASE
As the tachyzoites actively grow, increase in number, and eventually rupture from the cell, they invade adjacent cells. This process creates additional lesions. Once the cysts are formed, the process becomes quiescent, with little or no multiplication and spread. In the immunocompromised or immunodeficient patient, a cyst rupture or primary exposure to the organisms often leads to lesions. The organisms can be disseminated via the lymphatic system and the bloodstream to other tissues.
Toxoplasmosis can be categorized into four groups: (1) acquired in the immunocompetent patient; (2) acquired or reactivated in the immunodeficient patient; (3) congenital; and (4) ocular.
Diagnosis and their interpretations may differ for each clinical category.
Immunocompetent Individuals
In almost all cases, no clinical symptoms are seen during the acute infection. However, 10% to 20% of these patients with acute infection may develop painless cervical lymphadenopathy and a flulike illness. This presentation is self-limited with symptoms resolving within weeks to months. Acute visceral manifestations are seen in rare cases. The majority of these patients remain asymptomatic or consider they have experienced nothing more than a common cold.
Immunocompromised Individuals Infections in the compromised patient can lead to severe complications (Table 50-4). Underlying conditions that may impact the disease outcome include Hodgkin’s disease, non-Hodgkin’s lymphomas, leukemia, solid tumors, collagen vascular disease, organ transplantation, and AIDS. In the immunocompromised patient, the CNS is primarily involved, but these patients may also have myocarditis or pneumonitis. More than 50% of these patients will show altered mental state, motor impairment, seizures, abnormal reflexes, and other neurologic sequelae. Toxoplasmosis in patients being treated with immunosuppressive drugs may be due to either newly acquired or reactivated latent infection.
Table1. People at Risk for Severe Toxoplasmosis
In transplant recipients, the disease presentation depends on prior exposure to T. gondii by the donor and recipient, the type of organ involved, and the patient’s level of immunosuppression. Reactivation of a latent infection or an acute primary infection acquired directly from the transplanted organ can lead to severe disease. Stem cell transplant (SCT) recipients are particularly susceptible to severe toxoplasmosis, primarily attributable to reactivation of a previously acquired latent infection.
Before the use of highly active antiretroviral therapies (HAARTs), Toxoplasma encephalitis (TE) was a life threatening opportunistic infection among patients with AIDS and was usually fatal if not treated. In AIDS patients with reactivated latent infections, psychiatric manifestations of T. gondii are seen, including altered mental status (60%) with delusions, auditory hallucinations, and thought disorders. T. gondii enhances HIV-1 replication within reservoir host cells and, at the same time, HIV-1 undermines acquired immunity to the parasite, promoting reactivation of chronic toxoplasmosis.
Congenital Infections
Congenital infection results when the mother acquires a primary infection during pregnancy. The majority of patients remain asymptomatic during the acute infection. However, congenital infections may be severe if the mother becomes infected during the first or second trimester. At birth or soon thereafter, symptoms in these infants may include retinochoroiditis, cerebral calcification, and occasionally hydrocephalus or microcephaly. Because treatment of the mother may reduce the severity of disease in the infant, prompt and accurate diagnosis is mandatory. Many infants who are asymptomatic at birth will subsequently develop symptoms of congenital toxoplasmosis; however, treatment may help prevent sub sequent sequelae. Central nervous system involvement may not appear until several years later.
Ocular Infections
Ocular toxoplasmosis, an important cause of chorioretinitis, may be the result of congenital or acquired infection, acquired infection being more common than congenital infection. Patients with congenital infection may be asymptomatic until the second or third decade; at that point, cysts may rupture with lesions and develop in the eye. Chorioretinitis is characteristically bilateral in patients with congenital infection but is often unilateral in individuals with acute acquired T. gondii infection.
LABORATORY DIAGNOSIS
The most common method of diagnosis for toxoplasmosis is serologic testing for T. gondii– specific antibodies. Other procedures include PCR; examination of biopsy specimens, buffy coat cells, or cerebrospinal fluid; or isolation of the organism in tissue culture or in laboratory animals. It is important to remember that many individuals have been exposed to T. gondii and may have cysts within the tissues. Recovery of organisms from tissue culture or animal inoculation may be misleading, because the organisms may be isolated but may not be the etiologic agent of disease. However, two situations in which organism detection may be very significant are (1) tachyzoites in smears and/or tissue cultures inoculated from cerebrospinal fluid and (2) tachyzoites in patients with acute pulmonary disease and the demonstration of intracellular and extracellular tachyzoites in Giemsa-stained smears of bronchoalveolar lavage (BAL) fluid.
When laboratory personnel decide to initiate Toxoplasma-specific antibody testing or switch to a different antibody detection kit, the user must carefully review the manufacturer’s package insert and published literature for information on the sensitivity and specificity rates.
An in-laboratory comparison of kits should be per formed, using positive and negative samples confirmed by a toxoplasmosis reference laboratory.
The serologic diagnosis of toxoplasmosis is very complex and has been discussed extensively in the literature (Wilson & McAuley, 2003); a number of additional procedures include enzyme immunoassays, enzyme linked immunosorbent assays (ELISAs), direct agglutination, an immunosorbent agglutination assay, an indirect immunofluorescence assay (IFA), immunocapture, and immunoblot tests.
THERAPY
Treatment is recommended for the following conditions: clinically active disease, diagnosed congenital toxoplasmosis in newborns, pregnant women with infection during gestation, patients with chorioretinitis, and disease in symptomatic compromised patients. Therapy is also recommended for preventive or suppressive treatment in HIV-infected persons. The currently recommended drugs work primarily against the actively dividing tachyzoite form of T. gondii and do not eradicate encysted organisms (bradyzoites).
The most common drug combination used to treat congenital toxoplasmosis consists of pyrimethamine and a sulfonamide (sulfadiazine is recommended in the United States), plus folinic acid in the form of leucovorin calcium to protect the bone marrow from the toxic effects of pyrimethamine. Spiramycin is recommended for pregnant women with acute toxoplasmosis when fetal infection has not been confirmed in an attempt to prevent transmission of T. gondii from the mother to the fetus.
In immunosuppressed persons with toxoplasmosis, the combination of pyrimethamine and sulfadiazine plus leucovorin is the preferred treatment. Clindamycin is a second alternative for use in combination with pyrimethamine and leucovorin in those who cannot tolerate sulfonamides. Because relapse often occurs after toxoplasmosis in HIV-infected patients, maintenance therapy with pyrimethamine plus sulfadiazine or pyrimethamine plus clindamycin is recommended. For prophylaxis to prevent an initial episode of toxoplasmosis in Toxoplasma seropositive persons with CD4+ T-lymphocyte counts of less than 100 cells/mL, trimethoprim-sulfamethoxazole is recommended as the first choice, with alternatives consisting of dapsone plus pyrimethamine or atovaquone with or without pyrimethamine. Leucovorin is given with all regimens, including pyrimethamine. HIV-infected persons who are serologically negative for Toxoplasma IgG should be advised to protect themselves from primary infection by eating well-cooked meats and washing their hands after possible soil contact. Cats kept as pets should be fed commercial or well-cooked food, should be kept indoors, and should have their litter box changed each day.
Pyrimethamine and sulfadiazine are often used for persons with ocular disease. Clindamycin, in combination with other antiparasitic medications, is frequently used for the treatment of ocular disease. In addition to antiparasitic drugs, physicians may add corticosteroids to reduce ocular inflammation.
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