Toxoplasma

Toxoplasma gondii is an obligate intracellular apicomplexan parasite with an extremely wide host range, capable of infecting virtually any warm-blooded animal.

It is one of the most prevalent parasitic infections of humans worldwide. Seroprevalence in many populations exceeds a third to half of adults, the large majority of whom have asymptomatic or unrecognised chronic infection.

Felids, domestic cats and their wild relatives, are the only definitive hosts of Toxoplasma gondii. Sexual reproduction of the parasite occurs exclusively within the feline intestinal epithelium.

A cat typically becomes infected by ingesting tissue cysts (most commonly by hunting and eating infected rodents or birds) or, less commonly, oocysts.

Within the cat's small intestine, the parasite undergoes both asexual and sexual reproductive cycles in intestinal epithelial cells. This culminates in the production of unsporulated oocysts, shed in the cat's faeces, typically for one to two weeks following primary infection. After this, the cat generally develops sufficient immunity to prevent significant further oocyst shedding even if reinfected.

All other hosts, including humans, are intermediate hosts, in which only asexual replication occurs.

Oocysts shed in cat faeces are not immediately infective. They require a period of maturation in the environment (sporulation), typically one to several days under suitable warm, humid, aerobic conditions.

They then become infective. A highly resistant oocyst wall lets them remain viable and infective in soil, water, and on vegetation for many months to over a year.

Human infection via the oocyst route occurs through:

• accidental ingestion
• handling contaminated soil or cat litter without adequate hand hygiene
• consuming unwashed fruit or vegetables contaminated with sporulated oocysts
• drinking contaminated water

This is the basis of the standard advice to pregnant women to avoid cleaning cat litter trays, or to use gloves and wash hands thoroughly if unavoidable.

Tissue cysts are the form responsible for the second major route of human infection. This is consumption of undercooked or raw meat (particularly pork, lamb, and to a lesser extent beef and game meat) containing tissue cysts.

The cysts harbour slowly dividing bradyzoites within skeletal muscle, cardiac muscle, and neural tissue of infected intermediate hosts, including livestock.

Tissue cysts are resistant to the low temperatures of typical refrigeration. They are killed by adequate cooking temperatures and by freezing to sufficiently low temperatures for sufficient duration. This underlies dietary prevention advice for at-risk individuals, particularly pregnant women and the immunosuppressed.

The tachyzoite is the rapidly dividing, actively invasive, extracellular-to-intracellular form responsible for acute infection and tissue damage.

Following ingestion of oocysts or tissue cysts, released sporozoites or bradyzoites convert to tachyzoites. These invade host cells (essentially any nucleated cell type) and replicate rapidly by endodyogeny (internal budding producing two daughter cells) within an intracellular parasitophorous vacuole. They cause direct cytolytic destruction of the host cell upon release.

They then disseminate via blood and lymphatics to infect further tissues throughout the body. This includes crossing the placental barrier (transplacental transmission) and the blood-brain barrier.

As the host immune response develops and controls active tachyzoite replication, the parasite converts to the bradyzoite form, a slowly dividing, metabolically quiescent form that encysts within host tissue, forming the tissue cyst, most characteristically within neural tissue (brain) and skeletal and cardiac muscle.

Tissue cysts containing bradyzoites can persist for the lifetime of the host, representing a state of chronic, clinically latent infection under ordinary immune surveillance, with the potential to reactivate (bradyzoites converting back to tachyzoites) if host immune control is subsequently lost.

Congenital toxoplasmosis results from primary maternal infection (tachyzoite dissemination and parasitaemia) during pregnancy, with tachyzoites crossing the placenta to infect the fetus.

Women with chronic, previously acquired infection before conception are protected from transmitting infection to the fetus in a subsequent pregnancy, in essentially all cases involving an immunocompetent mother. Established immunity prevents the tachyzoite dissemination required for transplacental spread.

The risk of transmission to the fetus increases with advancing gestational age at the time of maternal infection. It is lowest in the first trimester, rises progressively through pregnancy, and reaches its highest rate in the third trimester. Severity of fetal disease follows the inverse pattern: earlier gestational infection produces more severe disease.

Classic manifestations of severe congenital toxoplasmosis include the triad of chorioretinitis, intracranial calcifications, and hydrocephalus. Other possible features include microcephaly, seizures, and systemic involvement (hepatosplenomegaly, jaundice, thrombocytopenia).

The majority of congenitally infected infants are asymptomatic at birth. If untreated, they are at risk of developing sequelae, particularly chorioretinitis, later in childhood or even adulthood. This underlies the rationale for prenatal and neonatal screening programmes in some countries.

In individuals with impaired cell-mediated immunity, dormant bradyzoite-containing tissue cysts can reactivate. Bradyzoites convert back to actively replicating, tissue-destructive tachyzoites.

The classic setting is advanced HIV infection with low CD4 counts. Transplant recipients on immunosuppressive therapy and others with significant T-cell dysfunction are also affected.

Reactivation is the dominant clinical pattern of toxoplasmosis in immunocompromised hosts. It is far more common than primary infection causing severe disease in this population, reflecting the very high background seroprevalence of latent infection in many populations.

Reactivation toxoplasmosis in HIV/AIDS is a recognised AIDS-defining illness. It occurs predominantly at low CD4 counts (classically below 100 cells/microlitre). This underlies the rationale for prophylaxis in seropositive patients with advanced immunosuppression.

The central nervous system is the most common and clinically important site of reactivation disease. It produces toxoplasmic encephalitis, which characteristically presents with focal neurological deficits, headache, fever, altered mental status, and seizures. The focal deficits reflect the tendency of Toxoplasma to form discrete, often multiple, space-occupying lesions rather than diffuse encephalitis.

Imaging classically demonstrates multiple ring-enhancing lesions, often with surrounding oedema. They are typically located in the basal ganglia and at the grey-white matter junction.

This pattern forms a key differential diagnosis (particularly in HIV-positive patients) alongside primary CNS lymphoma. The two can be difficult to distinguish on imaging alone. Assessment of treatment response to empirical anti-toxoplasma therapy, or additional imaging/biopsy, is sometimes needed when the diagnosis remains uncertain.

Ocular disease (toxoplasmic chorioretinitis) can occur as a manifestation of congenital infection, reactivation, or occasionally acquired postnatal infection. It produces focal retinal necrosis, vision loss, and characteristic funduscopic findings. It is a recognised cause of posterior uveitis in both immunocompetent and immunocompromised individuals.

Serology (detection of IgG and IgM antibodies against Toxoplasma) is the principal diagnostic method for establishing infection status. It distinguishes chronic/latent infection (IgG positive, IgM negative, consistent with past infection) from recently acquired infection (IgM positive).

IgG avidity testing helps distinguish recent from more distant infection. Low-avidity IgG suggests infection within the preceding few months. High-avidity IgG suggests infection more than several months prior.

This distinction is of particular importance in pregnancy, where the timing of maternal infection relative to conception and gestational age determines fetal risk and management.

In suspected congenital infection, amniotic fluid PCR for Toxoplasma DNA is used to assess fetal infection status following confirmed or suspected maternal primary infection during pregnancy. Neonatal diagnostic evaluation includes serology, PCR, and clinical/ophthalmological/neuroimaging assessment.

In reactivation disease (notably CNS toxoplasmosis in immunocompromised hosts), diagnosis is often made presumptively on the combination of:

• positive Toxoplasma IgG serology (indicating prior infection and therefore risk of reactivation)
• compatible clinical presentation
• characteristic imaging findings

This is frequently supported by a favourable clinical and radiological response to empirical treatment. PCR on cerebrospinal fluid or other tissue, and occasionally brain biopsy in atypical or non-responding cases, are used when the diagnosis remains uncertain.