eMedicine Specialties > Infectious Diseases > Parasitic Infections

Toxoplasmosis

Murat Hökelek, MD, PhD, Technical Consultant of Parasitology Laboratory, Associate Professor, Department of Clinical Microbiology, Ondokuz Mayis University Medical School, Turkey

Updated: Jan 27, 2009

Introduction

Background

Toxoplasmosis is caused by infection with Toxoplasma gondii, an obligate intracellular parasite. The infection produces a wide range of clinical syndromes in humans, land and sea mammals, and various bird species. T gondii has been recovered from locations throughout the world, except Antarctica. Nicolle and Manceaux first described the organism in 1908 after they observed the parasites in the blood, spleen, and liver of a North African rodent, Ctenodactylus gondii. The parasite was named Toxoplasma (arclike form) gondii (after the rodent) in 1909. In 1923, Janku reported parasitic cysts in the retina of an infant who had hydrocephalus, seizures, and unilateral microphthalmia. Wolf, Cowan, and Paige (1937-1939) determined that these findings represented the syndrome of severe congenital T gondii infection.

T gondii infects a large proportion of the world's population but uncommonly causes clinically significant disease. However, certain individuals are at high risk for severe or life-threatening toxoplasmosis. Individuals at risk for toxoplasmosis include fetuses, newborns, and immunologically impaired patients. Congenital toxoplasmosis is usually a subclinical infection. Among immunodeficient individuals, toxoplasmosis most often occurs in those with defects of T-cell–mediated immunity, such as those with hematologic malignancies, bone marrow and solid organ transplants, or AIDS.

In most immunocompetent individuals, primary or chronic (latent) T gondii infection is asymptomatic. A small percentage of these patients eventually develop chorioretinitis, lymphadenitis, or, rarely, myocarditis and polymyositis.

T gondii has 2 distinct life cycles. The sexual cycle occurs only in cats, the definitive host. The asexual cycle occurs in other mammals (including humans) and various strains of birds. It consists of 2 forms, known as tachyzoites (the rapidly dividing form observed in the acute phase of infection) and bradyzoites (the slowly growing form observed in tissue cysts). The sexual cycle begins in the gastrointestinal tract of the cat. Macrogametocytes and microgametocytes develop from ingested bradyzoites and fuse to form zygotes. The zygotes then become encapsulated within a rigid wall and are shed as oocysts. The zygote sporulates and divides to form sporozoites within the oocyst. Sporozoites become infectious 24 hours or more after the cat sheds the oocyst via feces. During a primary infection, the cat can excrete millions of oocysts daily for 1-3 weeks. The oocysts are very strong and may remain infectious for more than one year in warm humid environments.

T gondii oocysts, tachyzoites, and bradyzoites can cause infection in humans. Infection can occur by ingestion of oocysts following the handling of contaminated soil or cat litter or the consumption of contaminated water or food sources (eg, unwashed garden vegetables). Transmission of tachyzoites to the fetus can occur via the placenta following primary maternal infection. Rarely, infection by tachyzoites occurs from ingestion of unpasteurized milk or by direct entry into the bloodstream through a blood transfusion or laboratory accident. Transmission can occur via ingestion of tissue cysts (bradyzoites) in undercooked or uncooked meat or through transplantation of an organ that contains tissue cysts. In Europe and the United States, pork is the major source of T gondii infection in humans.

Pathophysiology

T gondii oocysts are ingested in material contaminated by feces from infected cats. Oocysts may also be transported to food by flies and cockroaches. When the organism is ingested, bradyzoites are released from cysts or sporozoites are released from oocysts, and the organisms enter gastrointestinal cells. Host cell receptors consisting of laminin, lectin, and SAG1 are involved in T gondii tachyzoite attachment and penetration. Tachyzoites multiply, rupture cells, and infect contiguous cells. They are transported via the lymphatics and are disseminated hematogenously throughout the tissues.

The ability of T gondii to actively penetrate host cells results in formation of a parasitophorous vacuole that is derived from the plasma membrane, which is entirely distinct from a normal phagocytic or endocytic compartment.¹ Following apical attachment, the parasite rapidly enters the host cell in a process that is significantly faster than phagocytosis. The vacuole is formed primarily by invagination of the host cell plasma membrane, which is pulled over the parasite through the concerted action of the actin-myosin cytoskeleton of the parasite. During invasion, the host cell is essentially passive and no change is detected in membrane ruffling, the actin cytoskeleton, or phosphorylation of host cell proteins.

Tachyzoites proliferate, producing necrotic foci surrounded by a cellular reaction. Upon the development of a normal immune response, tachyzoites disappear from tissues. In immunodeficient individuals and in some apparently immunologically healthy patients, the acute infection progresses, resulting in potentially lethal consequences such as pneumonitis, myocarditis, and necrotizing encephalitis.

Tissue cysts form as early as 7 days after infection and remain for the lifespan of the host. The tissue cysts are up to 60 μm in diameter, each containing up to 60,000 organisms. They produce little or no inflammatory response but cause recrudescent disease in immunocompromised patients or chorioretinitis in congenitally infected older children.

When a mother is infected with T gondii during gestation, the parasite may be disseminated hematogenously to the placenta. When this occurs, infection may be transmitted to the fetus transplacentally or during vaginal delivery. If the mother acquires the infection in the first trimester and it goes untreated, the risk of infection to the fetus is approximately 14-17%, and toxoplasmosis in the infant is usually severe. If the mother is infected in the third trimester and it goes untreated, the risk of fetal infection is approximately 59-65%, and involvement is mild or inapparent at birth. These different rates of transmission are most likely related to placental blood flow, the virulence and amount of T gondii acquired, and the immunologic ability of the mother to restrict parasitemia.

The most significant manifestation of toxoplasmosis in the fetus is encephalomyelitis, which may have severe results. Approximately 10% of prenatal T gondii infections result in abortion or neonatal death. In approximately 67-80% of prenatally infected infants, the infection is subclinical and can be diagnosed using only serological and other laboratory methods. Although these infants appear healthy at birth, they may develop clinical symptoms and deficiencies later in life.

Some infants with more severe congenital infection appear to have Toxoplasma antigen–specific lymphocytic anergy, which may be important in the pathogenesis of their disease. Monoclonal gammopathy of the immunoglobulin G (IgG) class has been described in congenitally infected infants, and immunoglobulin M (IgM) levels may be elevated in newborns with congenital toxoplasmosis. Glomerulonephritis with deposits of IgM, fibrinogen, and Toxoplasma antigen has been reported in congenitally infected individuals.

Circulating immune complexes have been detected in sera from an infant with congenital toxoplasmosis and in older individuals with systemic, febrile, and lymphadenopathic forms of toxoplasmosis. However, these complexes did not persist after signs and symptoms resolved. Total serum levels of immunoglobulin A may be diminished in congenitally infected babies, but no predilection toward associated infections has been noted. The predilection toward predominant involvement of the CNS and retina in this congenital infection has not been fully explained.

Alterations in subpopulations of T lymphocytes are profound and prolonged during acute acquired T gondii infection. These have been correlated with disease syndromes but not with disease outcome. Some patients with prolonged fever and malaise have lymphocytosis, increased suppressor T-cell counts, and a decreased helper-to-suppressor T-cell ratio. These patients may have fewer helper cells even when they are asymptomatic. In some patients with lymphadenopathy, helper cell counts are diminished for more than 6 months after infection onset. Ratios of T-cell subpopulations may also be abnormal in asymptomatic patients. Some patients with disseminated toxoplasmosis have a very marked reduction in T cells and a marked depression in the ratio of helper to suppressor T lymphocytes. Depletion of inducer T-lymphocytes in patients with AIDS may contribute to the severe manifestations of toxoplasmosis observed in these patients.

Frequency

United States

Serologic surveys indicate that 3-70% of healthy adults in the United States have been infected with T gondii. Cultural habits of a population may affect the acquisition of T gondii infection from ingested tissue cysts in undercooked or uncooked meat. In general, the incidence of the infection varies by population group and geographic locale studied. The prevalence of T gondii antibodies in US military recruits decreased by one third from 1965-1989; the crude seropositivity rate among recruits from 49 states was 9.5% in 1989 compared with 14.4% in 1965. T gondii infection affects more than 3500 newborns in the United States each year. T gondii seropositivity rates among patients with HIV infection vary from 10-45%.

Toxoplasmic encephalitis (TE) has been reported in 1-5% of patients with AIDS. Toxoplasmic encephalitis has been reported to be the index AIDS diagnosis in 44-58% of HIV-infected patients with TE. Within the United States, significant differences are recognized in the incidence of toxoplasmic encephalitis, both in different geographic regions and among various ethnic groups. Toxoplasmosis in patients with AIDS is reported to occur 3 times more frequently in Florida than in other areas of the United States; in patients of Haitian origin with AIDS who live in Florida, 12-40% develop toxoplasmic encephalitis.

Approximately 225,000 cases of toxoplasmosis are reported each year, resulting in 5000 hospitalizations and 750 deaths, making T gondii the third most common cause of lethal foodborne disease in the United States.

International

In many populations, such as those in El Salvador and France, the seropositivity rate to T gondii is as high as 75% by the fourth decade of life. As many as 90% of adults in Paris are seropositive. Approximately 50% of the adult population in Germany is infected. Women of childbearing age in much of Western Europe, Africa, and South and Central America have seroprevalence rates of greater than 50%. Based on serological studies, recent estimates suggest the incidence of primary maternal T gondii infection during pregnancy ranges from about 1 to 310 per 10,000 pregnancies in different populations in Europe, Asia, Australia, and the Americas. The incidence of prenatal T gondii infection within the same or similar populations have been estimated to range from about 1 to 120 per 10,000 births.

In individuals with HIV infection, the seropositivity rate to T gondii is approximately 50-78% in certain areas of Western Europe and Africa.

Toxoplasmic encephalitis is the AIDS-defining diagnosis in 16% of patients with AIDS. In France, 37% of patients with AIDS have evidence of toxoplasmic encephalitis at autopsy.

The prevalence rate in different provinces ranged from 0.3-11.8% in China.²

Mortality/Morbidity

• Acute toxoplasmosis is asymptomatic in 80-90% of healthy hosts. In some apparently immunologically healthy patients, the acute infection progresses and may cause potentially lethal consequences.
• Toxoplasmosis is recognized as a major cause of neurologic morbidity and mortality among patients with advanced HIV disease.
• Similar to other opportunistic pathogens, T gondii causes asymptomatic or mildly symptomatic infections in healthy hosts but rapidly progressive, fatal disease in immunosuppressed patients.

Race

• The highest incidence of toxoplasmosis among US patients with AIDS is in emigrants from Haiti (11.2%).

Sex

• Toxoplasmosis does not have a significant sexual predilection.

Age

• The prevalence of T gondii antibodies increases with age.
• The seroconversion rate in women of childbearing age is 0.8% per year. The risk of transplacental transmission is greatest during the third trimester of pregnancy.
• Children with acute congenital toxoplasmosis often die in the first month of life. Subacute congenital toxoplasmosis may not be observed until some time after birth, when symptoms start to appear.
• For additional information on pediatric toxoplasmosis, see the article Toxoplasmosis in eMedicine’s Pediatrics: General Medicine volume.

Clinical

History

Only 10-20% of toxoplasmosis cases in adults and children are symptomatic. Toxoplasmosis is a serious and often life-threatening disease in immunodeficient patients. Congenital toxoplasmosis may manifest as a mild or severe neonatal disease, with onset during the first month of life or with sequelae or relapse of a previously undiagnosed infection at any time during infancy or later in life. Congenital toxoplasmosis has a wide variety of manifestations during the perinatal period.

• Acute toxoplasmosis in immunocompetent hosts
  • Approximately 80-90% of patients are asymptomatic.
  • Patients may have cervical lymphadenopathy with discrete, usually nontender, nodes smaller than 3 cm in diameter.
  • Fever, malaise, night sweats, and myalgias have been reported.
  • Patients may have a sore throat.
  • Retroperitoneal and mesenteric lymphadenopathy with abdominal pain may occur.
  • Chorioretinitis is reported.
• Acute toxoplasmosis in hosts who do not have AIDS but are immunodeficient
  • Disease may be newly acquired or may be a reactivation.
  • CNS toxoplasmosis occurs in 50% of patients,
  • Patients may have encephalitis, meningoencephalitis, or mass lesions.
  • Hemiparesis, seizures, and mental status changes are reported.
  • Patients may report visual changes.
  • They may have signs and symptoms similar to those observed in immunocompetent hosts.
  • Myocarditis and pneumonitis are reported.
• Clinical manifestations of toxoplasmosis in patients with AIDS
  • Brain involvement (ie, toxoplasmic encephalitis), with or without focal CNS lesions, is the most common manifestation of toxoplasmosis in individuals with AIDS.
    • Clinical findings include an altered mental state, seizures, weakness, cranial nerve disturbances, sensory abnormalities, cerebellar signs, meningismus, movement disorders, and neuropsychiatric manifestations.
    • The characteristic presentation is usually a subacute onset, with focal neurologic abnormalities in 58-89% of cases. However, in 15-25% of cases, the clinical presentation is more abrupt, with seizures or cerebral hemorrhage.
    • Most commonly, hemiparesis and/or speech abnormality is the major initial manifestation.
    • Brain stem involvement often produces cranial nerve lesions, and many patients exhibit cerebral dysfunction with disorientation, altered mental state, lethargy, and coma.
    • Less commonly, parkinsonism, focal dystonia, rubral tremor, hemichorea-hemiballismus, panhypopituitarism, diabetes insipidus, or syndrome of inappropriate antidiuretic hormone secretion may dominate the clinical picture.
    • In some patients, neuropsychiatric symptoms such as paranoid psychosis, dementia, anxiety, and agitation may be the major manifestations.
    • Diffuse toxoplasmic encephalitis may develop acutely and can be rapidly fatal; generalized cerebral dysfunction without focal signs is the most common manifestation, and CT scan findings are normal or reveal cerebral atrophy.
    • Spinal cord involvement manifests as motor or sensory disturbances of single or multiple limbs, bladder or bowel dysfunctions, or both and local pain. Patients may present with clinical findings similar to those of a spinal cord tumor.
    • Cervical myelopathy, thoracic myelopathy, and conus medullaris syndrome have been reported.
  • Pulmonary toxoplasmosis (pneumonitis) due to toxoplasmosis is increasingly recognized in patients with AIDS who are not receiving appropriate anti-HIV drugs or primary prophylaxis for toxoplasmosis.
    • The diagnosis may be confirmed by demonstrating T gondii in bronchoalveolar lavage (BAL) fluid.
    • Pulmonary toxoplasmosis mainly occurs in patients with advanced AIDS (mean CD4⁺ count of 40 cells/µL ±75 standard deviation) and primarily manifests as a prolonged febrile illness with cough and dyspnea.
    • Pulmonary toxoplasmosis may be clinically indistinguishable from Pneumocystis jiroveci pneumonia, and the mortality rate, even when treated appropriately, may be as high as 35%.
    • Extrapulmonary toxoplasmosis develops in approximately 54% of persons with toxoplasmic pneumonitis.
  • Ocular toxoplasmosis, ie, toxoplasmic chorioretinitis, is relatively uncommon in patients with AIDS; it commonly manifests as ocular pain and loss of visual acuity.
    • Funduscopic examination usually demonstrates necrotizing lesions that may be multifocal or bilateral.
    • Overlying vitreal inflammation is often present and may be extensive.
    • The optic nerve is involved in as many as 10% of cases.
  • Other uncommon manifestations of toxoplasmosis in patients with AIDS include the following:
    • Panhypopituitarism and diabetes insipidus have been reported.
    • Multiple organs may be involved, and the disease manifests as acute respiratory failure and hemodynamic abnormalities similar to septic shock.
    • These patients may develop the syndrome of inappropriate antidiuretic hormone secretion and possibly orchitis.
    • Gastrointestinal system invasion of T gondii may result in abdominal pain, diarrhea, and/or ascites (due to involvement of the stomach, peritoneum, or pancreas).
    • Acute hepatic failure due to toxoplasmosis has been reported, as has musculoskeletal involvement.
• Congenital toxoplasmosis
  • This is most severe when maternal infection occurs early in pregnancy.
  • Approximately 15-55% of congenitally infected children do not have detectable T gondii –specific IgM antibodies at birth or early infancy.
  • Approximately 67% of patients have no signs or symptoms of infection.
  • Chorioretinitis occurs in about 15% of patients.
  • Intracranial calcifications develop in about 10%.
  • Cerebrospinal fluid (CSF) pleocytosis and elevated protein values are present in 20% of patients.
  • Infected newborns have anemia, thrombocytopenia, and jaundice at birth.
  • Microcephaly is reported.
  • Affected survivors may have mental retardation, seizures, visual defects, spasticity, or other severe neurologic sequelae.
• Ocular toxoplasmosis
  • Patients develop chorioretinitis (focal necrotizing retinitis).
  • They have a yellowish, white, elevated cotton patch with indistinct margins.
  • The lesions may occur in small clusters.
  • Congenital disease is usually bilateral.
  • Acquired disease is usually unilateral.
  • Symptoms include blurred vision, scotoma, pain, and photophobia.
  • For additional information on ocular manifestations of toxoplasmosis, see the article Toxoplasmosis in eMedicine’s Ophthalmology volume.

Physical

• The most common form of symptomatic acute toxoplasmosis in immunocompetent individuals is lymphadenopathy.
• The typical presentation is painless firm lymphadenopathy confined to one chain of nodes, most commonly cervical.
• The other physical manifestations include low-grade fever, hepatosplenomegaly, and rash.
• Ophthalmologic examination reveals multiple yellow-white cottonlike patches with indistinct margins located in small clusters in the posterior pole.
• A flare-up of congenitally acquired chorioretinitis is often associated with scarred lesions juxtaposed to the fresh lesion.
• Because of multifocal involvement of the CNS, clinical findings vary widely and include alterations in mental status, seizures, motor weakness, cranial nerve disorders, sensory abnormalities, cerebellar signs, meningismus, movement disorders, and neuropsychiatric manifestations in immunocompromised patients.

Causes

• The etiologic agent for each of the clinical syndromes is T gondii.
  • Congenital toxoplasmosis is passed transplacentally from the newly infected mother to the fetus during pregnancy.
  • Other syndromes may result from newly acquired T gondii infection or reactivation of latent infection.
  • Ingestion of raw meats or foods containing tissue cysts or oocysts present in cat feces can cause infection.
  • T gondii infection can be transmitted via blood transfusion or organ transplantation.
• Risk factors for T gondii infection include the following:
  • Immunocompromised hosts, especially those with defects in cellular immunity such as AIDS, are at increased risk of infection.
  • Slaughterhouse workers and butchers may be at an increased risk for infection.

Differential Diagnoses

Other Problems to Be Considered

Congenital toxoplasmosis -Rubella, encephalopathies, erythroblastosis fetalis
Toxoplasma encephalitis - Vasculitis, progressive multifocal leukoencephalopathy, tumor

Workup

Laboratory Studies

• The diagnosis of toxoplasmosis is confirmed with the demonstration of T gondii organisms in blood, body fluids, or tissue.
• Isolation of T gondii from amniotic fluid is diagnostic of congenital infection by mouse inoculation.
• Lymphocyte transformation to T gondii antigens is an indicator of previous toxoplasmosis in adults.
• Detection of T gondii antigen in blood or body fluids via enzyme-linked immunosorbent assay (ELISA) technique indicates acute infection.
• The Sabin-Feldman dye test is a sensitive and specific neutralization test for toxoplasmosis. It is used to measure primarily IgG antibody and is the standard reference test for toxoplasmosis. However, it requires live T gondii organisms; therefore, it is not available in most laboratories. High titers suggest acute toxoplasmosis.³
• The indirect fluorescent antibody test is used to measure the same antibodies as the dye test. Titers parallel dye test titers.
• The IgM fluorescent antibody test is used to detect IgM antibodies within the first week of infection, but titers fall within a few months.
• The indirect hemagglutination test is easy to perform. However, it usually does not detect antibodies during the acute phase of toxoplasmosis. Titers tend to be higher and remain elevated longer.
• The results from a double-sandwich IgM ELISA are more sensitive and specific than the results from other IgM tests.
• The results of the IgG avidity test may help differentiate those with acute infection from those with chronic infections better than alternative assays, such as assays that measure IgM antibodies. As is true for IgM antibody tests, the avidity test is most useful when performed early in gestation because a long-term pattern occurring late in pregnancy does not exclude the possibility that the acute infection may have occurred during the first months of gestation.⁴
• Polymerase chain reaction on body fluids, including CSF, amniotic fluid, BAL fluid, and blood, may be useful in the diagnosis.

Imaging Studies

• Head CT scanning in cerebral toxoplasmosis (general)
  • In most immunodeficient patients with toxoplasmic encephalitis, CT scans show multiple bilateral cerebral lesions.
  • Although multiple lesions are more common in persons with toxoplasmosis, they may be solitary; a single lesion should not exclude toxoplasmic encephalitis as a diagnostic possibility.
  • MRI has superior sensitivity (particularly if gadolinium is used for contrast) to CT scanning, and MRIs often demonstrate a single or multiple lesion(s) or more extensive disease not apparent on CT scans.
  • Various positron emission tomography scanning, radionuclide scanning, and magnetic resonance techniques have been used to evaluate patients with AIDS who have focal CNS lesions and to specifically differentiate between toxoplasmosis and primary CNS lymphoma.
  • Ultrasonographic diagnosis of congenital toxoplasmosis in a fetus is available at 20-24 weeks' gestation.
• Head CT scanning in cerebral toxoplasmosis (in patients with AIDS)
  • CT scans in patients with AIDS who have toxoplasmic encephalitis reveal multiple ring-enhancing lesions in 70-80% of cases.
  • In patients with AIDS who have detectable Toxoplasma IgG and multiple ring-enhancing lesions on CT scans or MRIs, the predictive value for toxoplasmic encephalitis is approximately 80%.
  • Lesions tend to occur at the corticomedullary junction (frequently involving the basal ganglia) and are characteristically hypodense.
  • The number of lesions is frequently underestimated when assessed using CT scan images, although delayed imaging after a double dose of intravenous contrast material may improve the sensitivity of this modality.
  • An enlarging hypodense lesion that does not enhance is a poor prognostic sign.
  • Toxoplasmic encephalitis lesions on MRIs appear as high-signal abnormalities on T2-weighted studies and have a rim of enhancement surrounding the edema on T1-weighted contrast-enhanced images.
  • MRI has superior sensitivity (particularly if gadolinium is used for contrast) to CT scanning, and MRIs often demonstrate a lesion or lesions or more extensive disease not shown on CT scans. Hence, MRI should be used as the initial procedure when feasible (and especially if a single lesion is demonstrated on CT scan images). Nevertheless, even characteristic lesions on CT scans or MRIs are not pathognomonic of toxoplasmic encephalitis.
  • The major differential diagnosis of focal CNS lesions in patients with AIDS is CNS lymphoma, which manifests as multiple enhancing lesions in 40% of cases.
  • The probability of toxoplasmic encephalitis falls and the probability of lymphoma rises in the presence of single lesions on MRIs. Therefore, a brain biopsy may be required to obtain a definitive diagnosis in patients with a solitary lesion (especially if confirmed with MRI).
  • CT scanning abnormalities improve after 2-3 weeks of treatment in approximately 90% of patients with AIDS who have toxoplasmic encephalitis.
  • Complete resolution takes 6 weeks to 6 months; peripheral lesions resolve more rapidly than deeper ones.
  • Smaller lesions usually resolve completely within 3-5 weeks as shown on MRI, but lesions with a mass effect tend to resolve more slowly and leave a small residual lesion.
  • A radiologic response to therapy lags behind the clinical response, with better correlation by the end of acute therapy.

Other Tests

• Skin tests that show delayed skin hypersensitivity to T gondii antigens may be useful as a screening test.
• Antibody levels in aqueous humor or CSF may reflect local antibody production and infection at these sites.
• Perform amniocentesis at 20-24 weeks' gestation if congenital disease is suggested.

Histologic Findings

Histopathologic data of human toxoplasmosis has been obtained mostly from autopsy studies in infants and immunodeficient patients with serious infections. Such knowledge in immunocompetent patients is limited.

Pathological findings are usually obtained from lymph node biopsy specimens in these patients. Multiple brain abscesses are commonly found, often involving the cerebral cortex and deep gray nuclei, less often the brainstem and cerebellum, and rarely the spinal cord in the CNS.

In acute toxoplasmosis, lesions are composed of central necrotic foci with varying petechiae rounded by acute and chronic inflammation, vascular proliferation, and macrophage infiltration. Tachyzoites and bradyzoites in tissue cysts may be detected at the periphery of the necrotic foci. T gondii are commonly found on hematoxylin and eosin or Giemsa stains. However, parasites can be more easily described via immunohistochemical staining. The blood vessels in the area of necrotic lesions may demonstrate distinguished intimal proliferation or frank vasculitis with thrombosis and fibrinoid necrosis.

Chronic lesions are composed of small cystic fields containing a number of lipid- and hemosiderin-laden macrophages with surrounding gliosis. Parasites are difficult to find in older lesions.

Treatment

Medical Care

• Outpatient care is sufficient for acquired toxoplasmosis in immunocompetent hosts and in persons with ocular toxoplasmosis.
• Inpatient care is appropriate initially for persons with CNS toxoplasmosis and for acute toxoplasmosis in immunocompromised hosts.
• Treatment is usually unnecessary in asymptomatic hosts, except in children younger than 5 years.
• Symptomatic patients should be treated until immunity is ensured.

Consultations

In addition to an infectious diseases specialist, the following are other recommended consultations:

• Parasitologist
• Ophthalmologist
• Neurologist
• Radiologist
• Gynecologist
• Pediatrician

Diet

No special diet is required in patients with toxoplasmosis.

Activity

The level of activity in patients with toxoplasmosis depends on the severity of disease and the organ systems involved.

Medication

Currently recommended drugs in the treatment of toxoplasmosis act primarily against the tachyzoite form of T gondii; thus, they do not eradicate the encysted form (bradyzoite). Pyrimethamine is the most effective agent and is included in most drug regimens. Leucovorin (ie, folinic acid) should be administered concomitantly to prevent bone marrow suppression. Unless circumstances preclude using more than one drug, a second drug (eg, sulfadiazine, clindamycin) should be added. The efficacy of azithromycin, clarithromycin, atovaquone, dapsone, and cotrimoxazole is unclear; therefore, they should be used only as alternatives in combination with pyrimethamine. The most effective available therapeutic combination is pyrimethamine plus sulfadiazine or trisulfapyrimidines (eg, combination of sulfamerazine, sulfamethazine, and sulfapyrazine). These agents are active against tachyzoites and are synergistic when used in combination.

Careful attention to dosing regimen is necessary because it differs depending on patient variables (eg, immune status, pregnancy). Pyrimethamine may be used with sulfonamides, quinine, and other antimalarials and with other antibiotics.

Sulfonamide antimicrobials

These agents exert bacteriostatic action through competitive antagonism with PABA. Microorganisms that require exogenous folic acid and do not synthesize folic acid (pteroylglutamic acid) are not susceptible to the action of sulfonamides. Resistant strains are capable of using folic acid precursors or preformed folic acid. Sulfonamide antimicrobials exist as 3 forms in serum—free, conjugated (ie, acetylated and possibly others), and protein-bound. The free form is considered therapeutically active.

Sulfadiazine (Microsulfon)

Bacteriostatic agent having similar spectrum of activity. Acts synergistically with pyrimethamine to treat toxoplasmosis.

Dosing

Adult

Loading doses
AIDS: 0.5-1.5 g PO q6h for 1-2 d (with pyrimethamine)
No AIDS: 0.25-1 g PO q6h for 1-2 d (with pyrimethamine)
Maintenance doses
AIDS: 500 mg PO qid, administered with pyrimethamine 25 mg/d as life-long therapy
No AIDS: 75 mg/kg PO once; not to exceed 4 g; followed by 1-1.5 g PO q6h for 2-4 wk

Pediatric

Acquired toxoplasmosis
>1 year: 75 mg/kg/d PO once, followed by 50 mg/kg/d for 2-4 wk
Congenital toxoplasmosis
100 mg/kg/d PO once, followed by 100 mg/kg/d divided into 2 doses for 2-6 mo

Interactions

Increases effect of oral anticoagulants and oral hypoglycemic agents; effects are decreased when administered concurrently with PABA or PABA metabolites of drugs (eg, proparacaine, tetracaine, sunscreens, procaine); may increase hypoglycemic effect of oral hypoglycemic agents; increases phenytoin levels as much as 80%

Contraindications

Documented hypersensitivity; breastfeeding

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Do not use during pregnancy at term due to risk of kernicterus in newborn; teratogenic potential of most sulfonamides has not been thoroughly investigated in animals or humans; significant increased incidence of cleft palate and other bony abnormalities in offspring has been observed when certain sulfonamides of the short-, intermediate-, and long-acting types were administered to pregnant rats and mice in high oral doses (ie, 7-25 times the human dose); do not use in infants <2 y except in congenital toxoplasmosis; caution in impaired renal or hepatic function and severe allergy or bronchial asthma; dose-related hemolysis may occur in G-6-PD deficiency; maintain adequate fluid intake to prevent crystalluria and stone formation; instruct patients to drink 8 oz of water with each dose and frequently throughout day
Caution patients to promptly report onset of sore throat, fever, pallor, purpura, or jaundice, which may indicate serious blood disorders; complete blood counts and urinalyses with careful microscopic examinations should be performed frequently; sulfonamides bear certain chemical similarities to some goitrogens (rats are especially susceptible to goitrogenic effects, and studies of long-term administration has produced thyroid malignancies in rats)

Dapsone (Avlosulfon)

Bactericidal and bacteriostatic against mycobacteria. Mechanism of action is similar to that of sulfonamides, ie, competitive antagonists of PABA prevent formation of folic acid, inhibiting bacterial growth.

Dosing

Adult

Prophylaxis of TE in AIDS: 50 mg/d PO (plus pyrimethamine)

Pediatric

>1 month: 1 mg/kg/d PO; not to exceed 100 mg

Interactions

May inhibit anti-inflammatory effects of clofazimine; hematologic reactions may increase with folic acid antagonists (eg, pyrimethamine), monitor for agranulocytosis during second and third mo of therapy; probenecid increases toxicity; concurrent trimethoprim may increase toxicity of both drugs; due to increased in renal clearance, dapsone levels may significantly decrease when administered concurrently with rifampin

Contraindications

Documented hypersensitivity; known G-6-PD deficiency

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Perform weekly blood counts (first mo), then perform WBC counts monthly (6 mo), then semiannually; discontinue if significant reduction in platelets, leukocytes, or hematopoiesis is observed; caution in methemoglobin reductase deficiency, G-6-PD deficiency (patients receiving >200 mg/d), or hemoglobin M due to high risk for hemolysis and Heinz body formation; caution in patients exposed to other agents or conditions (eg, infection, diabetic ketosis) capable of producing hemolysis; may cause peripheral neuropathy (rare) or phototoxicity when exposed to UV light

Lincosamide antimicrobials

These agents are used to treat serious skin and soft-tissue staphylococcal infections. They are also effective against aerobic and anaerobic streptococci (except enterococci). They inhibit bacterial growth, possibly by blocking dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest.

Clindamycin (Cleocin)

Alternative to sulfonamides. May be beneficial when used with pyrimethamine in acute treatment of CNS toxoplasmosis in AIDS patients.

Dosing

Adult

Loading dose
AIDS: 600 mg PO/IV q6h for 1-2 d (combined with pyrimethamine)
TE: 600 mg PO/IV q6h for 3-6 wk (combined with pyrimethamine)
Suppression: 300-450 mg PO q6-8h (combined with pyrimethamine)

Pediatric

8-20 mg/kg/d PO as hydrochloride (cap) or 8-25 mg/kg/d PO as palmitate (PO susp) divided tid/qid; not to exceed 1.8 g/d
20-40 mg/kg/d IV/IM divided tid/qid; not to exceed 4.8 g/d

Interactions

Increases duration of neuromuscular blockade induced by tubocurarine and pancuronium; erythromycin may antagonize effects; antidiarrheals may delay absorption

Contraindications

Documented hypersensitivity; regional enteritis; ulcerative colitis; hepatic impairment; antibiotic-associated colitis

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Adjust dose in severe hepatic dysfunction; no adjustment necessary in renal insufficiency; associated with severe and possibly fatal colitis by allowing overgrowth of Clostridium difficile

Antiprotozoal agents

Protozoal infections occur throughout the world and are a major cause of morbidity and mortality in some regions. Immunocompromised patients are especially at risk. Primary immune deficiency is rare, whereas secondary deficiency is more common. Immunosuppressive therapy, cancer and its treatment, HIV infection, and splenectomy may increase vulnerability to infection. Infectious risk is proportional to neutropenia duration and severity. Protozoal infections are typically more severe in immunocompromised patients than in immunocompetent patients.

Pyrimethamine (Daraprim)

Folic acid antagonist that selectively inhibits plasmodial dihydrofolate reductase. Highly selective against plasmodia and T gondii. Synergistic effect when used conjointly with a sulfonamide to treat toxoplasmosis.

Dosing

Adult

Loading dose
AIDS: 100-200 mg/d PO in combination with sulfadiazine 0.5-1.5 g PO q6h or clindamycin 600 mg PO q6h for 1-2 d
No AIDS: 50-200 mg/d PO in combination with sulfapyrimidine-type sulfonamide 0.25-1 g PO q6h for 2 doses
Maintenance dose
Immunocompetent: 25-50 mg/d PO for 2-4 wk
Immunocompromised (no AIDS): 25-50 mg/d PO for at least 4-6 wk
AIDS: 50-75 mg/d PO for 3-6 wk initially; followed by maintenance therapy of 25 mg/d PO as life-long therapy
Ocular: 25-50 mg/d PO for 4 wk
Congenital: 2 mg/kg/d PO for 2 d, then 1 mg/kg/d for 2-6 mo, then 1 mg/kg/d 3 times/wk for a minimum of 12 mo (in combination with sulfadiazine)
TE: 200 mg PO as a single dose initially, followed by 50-75 mg/d combined with sulfadiazine or clindamycin for at least 3 wk; as long as 6 wk or more may be required for severe disease
Prophylaxis/suppressive dose
AIDS: 50 mg/wk PO combined with dapsone 50 mg/d to prevent first episode of TE in AIDS patients; suppress with 25-75 mg/d PO plus clindamycin 300-450 mg PO q6-8h

Pediatric

2 mg/kg/d PO divided q12h for 2-4 d initially, then 1 mg/kg/d PO qd or divided q12h for 1 mo; not to exceed 25 mg/d

Interactions

Coadministration with other antifolate drugs (eg, sulfonamides, trimethoprim, sulfamethoxazole) may increase risk of bone marrow suppression; discontinue if folate deficiency develops; folinic acid (leucovorin) should be administered until normal hematopoiesis restored; coadministration with lorazepam may cause mild hepatotoxicity

Contraindications

Documented hypersensitivity; megaloblastic anemia due to folate deficiency

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Folic acid antagonist; most common adverse effect is dose-related bone marrow suppression, perform blood cell and platelet count twice weekly, decrease risk by concomitant administration of folinic acid (leucovorin), administer parenteral form of folinic acid 5-10 mg/d PO mixed with orange juice (as much as 50 mg/d used in AIDS patients); reduce initial dose in patients with convulsive disorders to avoid additive nervous system toxicity; caution in patients with impaired renal or hepatic function or possible folate deficiency (eg, malabsorption syndrome, alcoholism, pregnancy) and those receiving therapy (eg, phenytoin) that affects folate levels; may precipitate hemolytic anemia in G-6-PD deficiency, generally in presence of other stressful events; common adverse effects include nausea, vomiting, and abdominal cramps; caution with sun exposure, reports of photosensitivity

Atovaquone (Mepron)

A hydroxynaphthoquinone that inhibits the mitochondrial electron transport chain by competing with ubiquinone at the ubiquinone-cytochrome-c-reductase region (complex III). Inhibition of electron transport by atovaquone results in inhibition of nucleic acid and ATP synthesis in parasites. Has shown activity against bradyzoites in animal models of toxoplasmosis.

Dosing

Adult

750 mg (5 mL) PO bid with food for 21 d

Pediatric

Not established

Interactions

May decrease levels of TMP/SMZ; may increase zidovudine serum levels; coadministration with rifampin or rifabutin may decrease levels

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in elderly and in hepatic and renal impairment; adverse effects include rash, pruritus, headache, and nausea

Macrolide antimicrobials

Spiramycin is a macrolide antibiotic with an antibacterial spectrum similar to erythromycin and clindamycin. It is bacteriostatic at serum concentrations but may be bactericidal at achievable tissue concentrations. The mechanism of action is unclear, but it acts on the 50S subunit of bacterial ribosomes and interferes with translocation. Absorption from the GI tract is irregular (20-50% of PO dose absorbed). Following PO administration, peak plasma levels are achieved within 2-4 h. Spiramycin has a longer half-life than erythromycin and sustains higher tissue levels.

Azithromycin (Zithromax)

Acts by binding to 50S ribosomal subunit of susceptible microorganisms and, thus, interfering with microbial protein synthesis. Nucleic acid synthesis is not affected.
Concentrates in phagocytes and fibroblasts as demonstrated by in vitro incubation techniques. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues. Treats mild-to-moderate microbial infections.

Dosing

Adult

500 mg PO on day 1, followed by 250 mg/d for the next 4 d
TE and AIDS: 1200-1500 mg PO qd for 3-6 wk

Pediatric

10 mg/kg PO day 1, not to exceed 500 mg/d, followed by 5 mg/kg days 2-5 (not to exceed 250 mg/d)

Interactions

May increase toxicity of theophylline, warfarin, and digoxin; effects are reduced with coadministration of aluminum and/or magnesium antacids; nephrotoxicity and neurotoxicity may occur when coadministered with cyclosporine

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Site reactions can occur with IV route; bacterial or fungal overgrowth may result from prolonged antibiotic use; may increase hepatic enzymes and cholestatic jaundice; caution in patients with impaired hepatic function, prolonged QT intervals, or pneumonia; caution in hospitalized, geriatric, or debilitated patients

Spiramycin (Rovamycine)

DOC for maternal or fetal toxoplasmosis. Alternative therapy in other patient populations when unable to use pyrimethamine and sulfadiazine.

Dosing

Adult

3 g/d PO divided bid/qid for 3 wk; discontinue for 2 wk, then repeat 5-wk cycles throughout pregnancy

Pediatric

50-100 mg/kg/d PO divided bid/qid for 3-4 wk

Interactions

Decreases bioavailability of carbidopa, leading to decrease of levodopa levels

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Cross-resistance between microorganism resistant to erythromycin and carbomycin; acute colitis is experienced in 1% of patients; GI toxicity most common adverse effect; IV administration associated with peripheral paresthesias, irritation at injection site, dysesthesia, giddiness, pain, stiffness, burning sensation, and hot flashes; long-term use may result in superinfection; caution in cardiovascular disease because may prolong QT; may elevate LFTs

Follow-up

Further Inpatient Care

• Standard precautions are recommended in patients with toxoplasmosis.

Further Outpatient Care

• Follow-up visits should be scheduled every 2 weeks until the patient is stable, then monthly during therapy.
• A CBC count should be performed weekly for first month, then every 2 weeks.
• Renal and liver function tests should be performed monthly.

Deterrence/Prevention

• Preventing toxoplasmosis is particularly important in seronegative immunocompromised patients and in pregnant women.
  • Avoid eating raw meat, unpasteurized milk, and uncooked eggs.
  • Wash hands after touching raw meat and after gardening or handling soil.
  • Wash fruits and vegetables.
  • Avoid contact with cat feces.
  • To attempt to prevent congenital toxoplasmosis, routine serologic screening of pregnant women has been performed in order to identify fetuses at risk of infection.
• Avoiding transfusions of blood products from a donor who is seropositive to a patient who is seronegative and immunocompromised is prudent, when feasible.
• If possible, recipients who are seronegative should receive transplanted organs from donors who are seronegative.
• Laboratorians can become infected via ingestion of sporulated T gondii oocysts from feline fecal specimens or via skin or mucosal contact with either tachyzoites or bradyzoites in human or animal tissue or culture. Laboratories should have established protocols for handling specimens that contain viable T gondii and for responding to laboratory accidents.

Complications

• Seizure disorder or focal neurologic deficits may occur in persons with CNS toxoplasmosis.
• Partial or complete blindness may occur in those with ocular toxoplasmosis.
• Multiple complications may occur in persons with congenital toxoplasmosis, including mental retardation, seizures, deafness, and blindness.

Prognosis

• Toxoplasmosis in immunodeficient patients often relapses if treatment is stopped.
• Treatment may prevent the development of untoward sequelae in both symptomatic and asymptomatic infants with congenital toxoplasmosis.

Patient Education

• Mothers with toxoplasmosis must be completely informed of potential consequences to the fetus.
• Explain prevention methods, eg, protecting children's play area from cat litter.
• For excellent patient education resources, visit eMedicine's Brain and Nervous System Center. Also, see eMedicine's patient education article Brain Infection.

Miscellaneous

Medicolegal Pitfalls

• Misdiagnosis of toxoplasmosis is possible.

Multimedia

Media file 1: Toxoplasmosis. Toxoplasma gondii tachyzoites (Giemsa stain).

Media file 2: Toxoplasmosis. Toxoplasma gondii tachyzoites in cell line.

Media file 3: Toxoplasma gondii in infected monolayers of HeLa cells (Giemsa stain).

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Keywords

toxoplasmosis, Toxoplasma gondii, T gondii, Toxoplasma infection, congenital toxoplasmosis, systemic toxoplasmosis, febrile toxoplasmosis, lymphadenopathic toxoplasmosis, pediatric toxoplasmosis, ocular toxoplasmosis, pulmonary toxoplasmosis, extrapulmonary toxoplasmosis, toxoplasmic pneumonitis, toxoplasmic chorioretinitis, Sabin-Feldman dye test, unilateral microphthalmia, tachyzoites, bradyzoites, pneumonitis, myocarditis, necrotizing encephalitis, brain abscess, toxoplasmic encephalitis, TE, diffuse toxoplasmic encephalitis, Toxoplasma encephalitis, cerebral toxoplasmosis, CNS toxoplasmosis

Contributor Information and Disclosures

Author

Murat Hökelek, MD, PhD, Technical Consultant of Parasitology Laboratory, Associate Professor, Department of Clinical Microbiology, Ondokuz Mayis University Medical School, Turkey
Murat Hökelek, MD, PhD is a member of the following medical societies: Turkish Society for Parasitology
Disclosure: Nothing to disclose.

Medical Editor

Douglas A Drevets, MD, Assistant Professor, Department of Medicine, Section of Infectious Disease, Oklahoma University Health Sciences Center
Douglas A Drevets, MD is a member of the following medical societies: American Association of Immunologists, American Society for Microbiology, Central Society for Clinical Research, and Christian Medical & Dental Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

John L Brusch, MD, FACP, Assistant Professor of Medicine, Harvard Medical School; Consulting Staff, Department of Medicine and Infectious Disease Service, Cambridge Health Alliance
John L Brusch, MD, FACP is a member of the following medical societies: American College of Physicians and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

CME Editor

Eleftherios Mylonakis, MD, Clinical and Research Fellow, Department of Internal Medicine, Division of Infectious Diseases, Massachusetts General Hospital
Eleftherios Mylonakis, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Society for Microbiology, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Chief Editor

Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital
Burke A Cunha, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous coauthor Amar Safdar, MD, FACP, FIDSA, to the development and writing of this article.

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