eMedicine Specialties > Infectious Diseases > Parasitic Infections

Toxoplasmosis

Author: Murat Hökelek, MD, PhD, Technical Consultant of Parasitology Laboratory, Associate Professor, Department of Clinical Microbiology, Ondokuz Mayis University Medical School, Turkey
Contributor Information and Disclosures

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.

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