Toxoplasma gondii

• Protozoan parasite associated with cats and raw beef mostly known for causing opportunistic infections and congenital infections

Background

Microbiology

• Protozoan parasite
• Organized into twelve haplotypes

Epidemiology

• Zoonotic disease with worldwide distribution
• Modes of transmission
  • Ingesting tissue cysts in meat, or oocytes in food or water
  • Solid organ transplantation, especially heart
  • Vertical or transplacental transmission
  • Case reports of lab-acquired needlestick transmission
  • Theoretical risk with blood transfusion
• Seroprevalence around 10-18% in Canada 12
  • As high as 60% in Nunavut, however 3
• There are large parts of South and Central America, as well as Pacific Islands, that have very high seroprevalence 4

Life Cycle

• The only definitive hosts are in the Felidae family, essentially housecats and their relatives
• Intermediate hosts are many, and include birds and rodents
• An infected cat sheds oocytes into the environment (for 1 to 3 weeks), where they spend 1 to 5 days sporulating
  • Each sporulated oocyst contains two sporocysts, and each sporocyst contains four sporozoites
• Intermediate hosts ingest the sporozoites, where they mature into tachyzoites
• Tachyzoites migrate to brain and muscle, where they encyst and become bradyzoites
• Bradyzoites are ingested by a cat, completing the life cycle

Pathophysiology

• Following ingestion, bradyzoites and sporozoites invade the small intestinal mucosa and develop into tachyzoites within the gut epithelium
• There, they insert themselves into monocytes and other nucleated cells
• Infected cells travel throughout the body, carrying the tachyzoite with them
• Infection triggers a Th-1 response

Clinical Manifestations

Immunocompetent

• Asymptomatic in 80% of primary infections
• Symptoms, when they occur, can involve fever, cervical lymphadenopathy (painless and rubbery), myalgias, and weakness/fatigue
  • May mimic infectious mononucleosis
• Can also cause chorioretinitis
• Severity of illness depends in part on genotype, with strain II in North America and Europe being less severe
  • Rarely, unusual strains may cause pneumonitis, myocarditis, meningoencephalitis, or polymyositis, and can lead to death

Immunocompromised

• May be from primary infection or, more commonly, reactivation
• Unlike in immunocompetent people, it is always a serious infection in the immunocompromised
• Major risk factor is cellular immunodeficiency, as in HIV and some immunosuppressive medications
  • In HIV, beware with CD4 < 100
• Typically presents with CNS involvement as encephalitis
  • Symptoms include fever, headache, lethargy, incoordination, ataxia, hemiparesis, loss of memory, dementia, or seizures
• Can also present with pneumonitis (especially with bone marrow transplant), chorioretinitis, or myocarditis, and rarely involves essentially any other organ

Pregnancy

• As with other immunocompetent people, it is largely asymptomatic
• Only half of women can identify a significant risk factor 5
• Risk of transmission to fetus is with parasitemia associated with primary infection, so women who are seropositive are not at risk of having a child with congenital infection

Congenital

• Refer to Congenital toxoplasmosis

Diagnosis

• Immunocompetent or pregnant women with primary infection: IgG/IgM serology, possibly with avidity testing for pregnant women
• Fetus, to rule out congenital infection following maternal primary infection: PCR of amniotic fluid
• Newborn, to rule out congenital infection: PCR of placenta or cord, or serology
• Immunocompromised patient, to diagnose cerebral or disseminated disease: PCR of blood, CSF, BAL, or tissue
• Patient with chorioretinitis: Parallel serologies from aqueous humour and serum, or PCR of aqueous humour

Serology

• ELISA IgG for prior exposure; ELISA IgM for acute infection
• IgM titres plateau within 1 month, and IgG within 2-3 months
• IgM is still detectable for months or years after infection
• IgM avidity testing can help to assess how recently the infection was acquired
  • Provides a measure of how tightly the antibodies bind, which is highest in early infection
  • A high avidity ratio (weak binding) suggests that the infection was acquired at least 4 months prior

PCR

• Not routinely done
• May be helpful from CSF or vitreous humour
• Not helpful on brain biopsy tissue

Management

• In general, in the setting of known HIV and one or more suspicious lesions, treat empirically for CNS toxoplasmosis and reassess with repeat imaging at around 10 days, at which time there should be some response
• First-line is a combination of pyrimethamine and sulfadiazine
  • Pyrimethamine (with folinic acid) is the backbone
    • Pyrimethamine 200 mg PO once followed by 50 mg PO daily if ≤60 kg or 75 mg PO daily if >60 kg
    • Leucovorin 10-25 mg PO daily
  • The second agent is typically sulfadiazine, which can be replaced with clindamycin if needed
    • Sulfadiazine 1000 mg PO q6h if ≤60 kg or 1500 mg PO q6h if >60 kg
    • Clindamycin 600 mg PO/IV qid
• Alternatives
  • TMP-SMX
  • Atovaquone 1500 mg PO bid + pyrimethamine
  • Atovaquone 1500 mg PO bid ± sulfadiazine
  • Azithromycin 900-1200 mg PO daily + pyrimethamine

HIV

• Pyrimethamine 200 mg PO once, followed by dose based on body weight:
  • Body weight ≤60 kg: pyrimethamine 50 mg PO daily + sulfadiazine 1000 mg PO q6h + leucovorin 10–25 mg PO daily (can increase to 50 mg daily or BID)
  • Body weight >60 kg: pyrimethamine 75 mg PO daily + sulfadiazine 1500 mg PO q6h + leucovorin 10–25 mg PO daily (can increase to 50 mg daily or BID)
• Alternatives
  • Pyrimethamine (with leucovorin) plus clindamycin 600 mg IV or PO q6h
  • TMP-SMX (TMP 5 mg/kg and SMX 25 mg/kg) (IV or PO) BID
  • Atovaquone 1500 mg PO BID + pyrimethamine (leucovorin)
  • Atovaquone 1500 mg PO BID + sulfadiazine
  • Atovaquone 1500 mg PO BID

Pregnancy

• To treat active disease in mother:
  • Pyrimethamine is relatively contraindicated in pregnancy as it is toxic before 14 weeks gestation
  • If life-threatening, should likely need treatment and consider abortion (if early in pregnancy)
• To prevent congenital toxoplasmosis:
  • Spiromycin 1 g q8h is safe throughout pregnancy, and decreases transmission to fetus, but is not enough to treat CNS disease
  • After fetal infection is confirmed around 18 weeks, pyrimethamine 50 mg bid for 2 days then 50 mg daily, plus sulfadiazine 75 mg/kg/d split bid for 2 days then 50 mg/kg bid, plus leucovorin 10-20 mg daily

Prevention

• Cats: hand hygiene after handling cat, use gloves and wash hands when handling litter, wash litter tray with hot >60ºC water, keep litter out of kitchen
• Soil: use gloves for gardening, wash hands after soil contact
• Water: avoid tap water in highly endemic countries, avoid ingestion of lake and river water
• Food: avoid raw oysters/clams/mussels, wash all vegetables/fruits/herbs, cook meat well down

Further Reading

• Epidemiology of and Diagnostic Strategies for Toxoplasmosis. Clin Microbiol Rev. 2012;25(2):264. doi: [10.1128/CMR.05013-11]