Toxoplasmosis

Toxoplasmosis is an infection caused by the protozoan parasite Toxoplasma gondii. Disease ranges from asymptomatic in the large majority of immunocompetent hosts to severe, life threatening encephalitis in immunocompromised patients and devastating congenital disease in the fetus.

Clinical significance and management vary fundamentally according to host immune status and, in pregnancy, gestational timing of maternal infection.

The parasite is acquired by:

• ingestion of oocysts from cat faeces contaminated soil or food
• consumption of undercooked meat containing tissue cysts
• transplacental transmission from a mother with primary infection during pregnancy

Pathophysiology and disease context

Following ingestion, the organism disseminates and forms latent tissue cysts, particularly within neural and muscular tissue. These persist for life under normal cell mediated immune control.

In the immunocompromised host, particularly those with advanced HIV infection and a low CD4 count, loss of this immune control allows reactivation of latent cysts. This is most clinically significant within the central nervous system, producing focal necrotising encephalitis.

In pregnancy, primary maternal infection can result in transplacental transmission to the fetus. The risk of transmission increases with advancing gestational age at the time of maternal infection, while the severity of resulting fetal disease decreases.

Acute infection in an immunocompetent host is asymptomatic in the great majority. A minority develop a self limiting mononucleosis like illness comprising fever, malaise and, characteristically, painless cervical lymphadenopathy. It generally resolves without specific treatment.

Toxoplasma encephalitis in immunocompromised patients is most commonly seen in advanced HIV infection with a CD4 count below 100 cells per microlitre. It presents with headache, fever, focal neurological deficit, seizures and altered mental status, developing over days to a few weeks. It reflects reactivation of latent cysts and formation of one or more focal necrotising brain lesions.

Ocular toxoplasmosis presents with eye pain, blurred vision and floaters, reflecting necrotising retinochoroiditis. It can occur as part of congenital infection presenting later in childhood or adulthood. It can also be a manifestation of reactivated or acquired infection in adults of any immune status.

Congenital toxoplasmosis, resulting from transplacental transmission, ranges from an asymptomatic infant at birth to severe disease at birth. An asymptomatic infant is still at risk of later manifestations, particularly chorioretinitis, developing over subsequent years.

Severe disease at birth shows the classical triad of chorioretinitis, hydrocephalus and intracranial calcification. The most severely affected infants also have hepatosplenomegaly, jaundice and thrombocytopenia. This generally reflects infection acquired earlier in gestation.

Serology (Toxoplasma specific immunoglobulin G and immunoglobulin M) is the mainstay of diagnosis in the immunocompetent host and for maternal screening in pregnancy. A positive immunoglobulin G and negative immunoglobulin M generally indicates past infection with established immunity.

A positive immunoglobulin M, particularly with a rising immunoglobulin G titre or low immunoglobulin G avidity on specialised testing, suggests recent infection. This is an important distinction in pregnancy given the differing implications for fetal risk.

Toxoplasma encephalitis in the immunocompromised host is typically diagnosed presumptively. The diagnosis rests on a compatible clinical presentation, characteristic imaging findings, and positive serum immunoglobulin G (though a negative result does not entirely exclude the diagnosis in this population). Most importantly, there is a clear clinical and radiological response to empirical treatment within one to two weeks.

Brain biopsy is reserved for cases failing to respond to empirical therapy as expected or where the diagnosis remains genuinely uncertain.

Magnetic resonance imaging in toxoplasma encephalitis characteristically shows multiple ring enhancing lesions, often with surrounding oedema, with a predilection for the basal ganglia and grey white matter junction. The appearance overlaps considerably with primary central nervous system lymphoma, an important differential particularly in HIV positive patients. The two conditions are frequently distinguished based on response to empirical anti toxoplasma treatment.

Prenatal diagnosis of suspected congenital infection uses amniotic fluid polymerase chain reaction testing for Toxoplasma deoxyribonucleic acid. It is generally performed from around eighteen weeks gestation and at least four weeks after presumed maternal infection to optimise sensitivity. Detailed fetal ultrasound assessment looks for structural abnormalities suggestive of severe infection.

Postnatal diagnosis of congenital infection combines:

• infant serology (with persistent or rising immunoglobulin G beyond the expected decline of passively transferred maternal antibody, together with infant specific immunoglobulin M or immunoglobulin A)
• polymerase chain reaction testing where available
• full clinical assessment including neuroimaging and ophthalmological examination

Immunocompetent adults and children with uncomplicated acute infection generally require no specific treatment, given the self limiting nature of the illness in this population. Treatment is reserved for severe or persistent symptoms, or where there is significant organ involvement.

Toxoplasma encephalitis is treated with pyrimethamine, given as a loading dose of 200 mg orally on day one, followed by a maintenance dose of 50 mg once daily (for patients weighing under 60 kg) or 75 mg once daily (for patients weighing 60 kg or more).

This is combined with sulfadiazine 1000 mg orally four times daily (for patients under 60 kg) or 1500 mg orally four times daily (for patients 60 kg or above). Folinic acid 10 to 25 mg once daily is given to prevent pyrimethamine associated bone marrow suppression. This is continued as the induction regimen for a minimum of six weeks, guided by clinical and radiological response.

Clindamycin 600 mg orally or intravenously four times daily, combined with pyrimethamine and folinic acid at the same doses, is an effective alternative regimen. It is particularly useful in patients with sulfa allergy, given comparable efficacy to the sulfadiazine based regimen.

Trimethoprim with sulfamethoxazole, dosed at 10 mg per kg per day of the trimethoprim component divided into two doses, is a further alternative regimen with reasonable evidence of efficacy. It is particularly useful given its wider availability and lower cost in many settings.

Following successful induction treatment, secondary prophylaxis (maintenance therapy) is continued at a reduced dose of the same regimen. This is typically pyrimethamine 25 to 50 mg once daily with sulfadiazine 500 to 1000 mg four times daily and folinic acid. It continues until immune reconstitution has occurred, defined as a CD4 count above 200 cells per microlitre maintained for at least six months on effective antiretroviral therapy.

Primary prophylaxis against toxoplasma encephalitis is indicated for HIV positive patients with a CD4 count below 100 cells per microlitre who have positive Toxoplasma immunoglobulin G. It uses trimethoprim with sulfamethoxazole 960 mg once daily (which also provides pneumocystis prophylaxis). It is discontinued once the CD4 count rises above 200 cells per microlitre for at least three months on antiretroviral therapy.

Corticosteroids are added for toxoplasma encephalitis with significant mass effect or midline shift causing raised intracranial pressure. Use them for the shortest effective duration and with close monitoring. They can mask response to specific antimicrobial treatment and, in the differential diagnosis context, produce a misleading apparent response in primary central nervous system lymphoma.

Maternal primary infection in pregnancy is treated with spiramycin 1 g three times daily, aiming to reduce the risk of transplacental transmission. If fetal infection is confirmed or strongly suspected on amniotic fluid testing, change to pyrimethamine, sulfadiazine and folinic acid (at doses adjusted for pregnancy). Pyrimethamine is generally avoided in the first trimester given teratogenic concerns. Manage under specialist maternal fetal medicine and infectious disease guidance.

Confirmed congenital toxoplasmosis in the infant is treated with a prolonged course, typically twelve months, of pyrimethamine and sulfadiazine with folinic acid at weight based paediatric doses. Corticosteroids are added for active chorioretinitis or significantly elevated cerebrospinal fluid protein. Treatment is under specialist paediatric infectious disease guidance, with regular full blood count monitoring throughout given the bone marrow suppressive potential of this regimen.

Ocular toxoplasmosis affecting or threatening the macula or optic nerve is treated with the same pyrimethamine and sulfadiazine based systemic regimen used for encephalitis, generally for four to six weeks. Corticosteroids and close ophthalmological monitoring are added. Treatment decisions for peripheral lesions not threatening central vision are made on an individualised basis given the potential for spontaneous resolution.

Prevention advice forms an important and often underemphasised component of management, particularly for pregnant women and immunocompromised individuals identified as seronegative and therefore susceptible to primary infection. It includes:

• thorough cooking of meat
• washing of fruit and vegetables
• avoiding contact with cat litter, or wearing gloves and washing hands thoroughly if contact is unavoidable
• gardening with gloves, given potential soil contamination