Luisa M. Stamm (E. Mylonakis, Editor)
DESCRIPTION 
- Toxoplasmosis is an infection caused by the intracellular protozoan Toxoplasma gondii.
- Infection is usually asymptomatic in immunocompetent patients.
- Severe infections usually occur in an immunocompromised patient or by the transplacental passage of parasites from an infected woman to fetus (congenital toxoplasmosis).
- When symptoms occur, they range from a mild, self-limited disease to a fulminant disseminated disease that affects the following:
- Central nervous system (CNS)
- Eyes
- Lymph nodes
- Skeletal or cardiac muscle
- Lungs
- Liver
EPIDEMIOLOGY
Incidence
- Toxoplasmosis in immunocompetent patients
- The incidence increases with age and is similar between sexes.
- Toxoplasmosis in HIV-infected patients
- The greatest incidence is seen among patients with a low CD4 T-cell count (<100 cells/mm3)
- In areas with high seroprevalence for toxoplasmosis, 25–50% of all AIDS patients, who are not receiving antiretroviral therapy or prophylaxis, will develop CNS toxoplasmosis.
- Congenital toxoplasmosis
- Only 1 of 5 pregnant women infected with T. gondii develops clinical signs.
- Women who are seropositive before pregnancy usually are protected.
- If the acute infection in an infected woman goes untreated, congenital infection occurs in approximately 15% of fetuses during the first trimester, 30% of fetuses during the second trimester, and 60% of fetuses during the third trimester.
- The earlier in the pregnancy the transmission, the more severe the outcome is.
Prevalence
The seroprevalence depends on geographic location and the age of the population. In the US, it varies between 3% to >50%, while in tropical countries and in areas of Western Europe, it is up to 90%.
RISK FACTORS
- Because cats are the definitive host of T. gondii, owning a cat is a risk factor for disease.
- Additional risk factors include eating undercooked meat or contaminated vegetables in areas of high prevalence.
- Seronegative patients receiving solid organs from seropositive donors are at risk for acquiring disease.
- Reactivation occurs in immunocompromised patients.
Genetics
- Basic research with mice suggest that genetic factors in the host contribute to disease caused by T. gondii.
- In particular, certain HLA class II genes correlate with particular outcomes of CNS toxoplasmosis in AIDS patients.
GENERAL PREVENTION
- HIV-infected patients
- All HIV-infected persons should be tested for IgG antibody to T. gondii soon after the diagnosis of HIV infection.
- Toxoplasma-seropositive patients with CD4 T-cell counts <100 cells/mm3 should receive prophylaxis for toxoplasmosis.
- The doses of trimethoprim–sulfamethoxazole (TMP/SMX) recommended for Pneumocystis carinii pneumonia appear also to be effective prophylaxis for T. gondii.
- A combination of dapsone and pyrimethamine with folinic acid or atovaquone is an alternative.
- Primary prophylaxis should continue until CD4 T-cell count is greater than 200 cells/mm3 for 3 months.
- Other immunocompromised patients
- Post transplantation of bone marrow and solid organs, high-risk patients should receive TMP/SMX.
- Pregnant patients
- Seronegative pregnant women and other individuals at risk should be advised not to eat raw or undercooked meat, unpasteurized dairy products and should wash fruits and vegetables well.
- They should wash their hands after contact with raw meat and contact with soil.
- They should wear gloves while changing a cat's litter box, or, preferably, it should be changed by a non-pregnant, HIV-negative person.
PATHOPHYSIOLOGY
- There are 2 stages in the life cycle of T. gondii:
- The sexual phase results in the formation of oocysts in the cat's intestine. Oocysts are excreted in the feces, sporulation occurs, and may remain infectious for many months.
- Sporulated oocysts are ingested by an intermediate host (e.g., a human). Bradyzoites or sporozoites are released and transform to rapidly dividing tachyzoites, which can infect any organ.
ETIOLOGY
- Cats are the definitive hosts for T. gondii.
- Humans and other animals, such as sheep and pigs, become infected when they ingest oocysts shed in the feces of cats.
- Additionally, humans become infected by eating raw or undercooked meat containing tissue cysts.
COMMONLY ASSOCIATED CONDITIONS
Serious disease is associated with immunocompromised states such as AIDS with CD4 T-cell count <100 cells/mm3, hematologic malignancy, solid organ transplant and those receiving immunosuppressive therapy with high-dose corticosteroids and TNF-
(tumor necrosis factor) inhibitors.
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HISTORY
- Immunocompetent Patients
- Immunocompetent patients who newly acquire infection are asymptomatic in 80–90% of cases. Among symptomatic patients, lymphadenopathy is the most common presentation. The clinical course is self-limited.
- Less common presenting symptoms are:
- Toxoplasma causes near about 30–35% of cases of chorioretinitis in the US. Interestingly, most cases are from congenital infection. Patients usually develop symptoms during the second and third decades of life. Patients may present with the following:
- Blurred vision
- Scotoma
- Ocular pain
- Photophobia
- Epiphora
- Immunocompromised Patients
- A newly acquired or reactivated infection in immunocompromised patients usually involves the CNS and, less often, the lung (pneumonitis), the eye (chorioretinitis), or the heart. Cases of gastrointestinal, liver, skin, or multiorgan involvement also have been reported.
- Symptoms of CNS infection are usually subacute and include the following:
- Headache
- Seizures
- Weakness or numbness
- Visual field complaints
- Confusion
- Imbalance
- Difficulty with speech
- Stiff neck
- Fever
- Extracerebral toxoplasmosis which is less common among patients with HIV infection involves the lungs and/or the eyes in more than 75% of the cases, and it may develop among patients seronegative for T. gondii.
- Toxoplasmic pneumonitis usually presents with fever, dyspnea, and nonproductive cough.
- Ocular toxoplasmosis presents with the same symptoms as in immunocompetent patients, but it can progress more rapidly.
- Congenital toxoplasmosis
- Presentation is variable. There may be no sequelae, or sequelae may develop at various times after birth.
- Premature infants may present with CNS or ocular disease.
- Full-term infants usually develop milder disease, with hepatosplenomegaly and lymphadenopathy.
PHYSICAL EXAM
- CNS infection is associated with cranial nerve defects, visual field defects, mental status changes, cerebellar signs, meningismus, and sensory or motor disturbances.
- In immunocompetent patients, cervical lymph nodes are most commonly involved, but any or all lymph node groups may be enlarged. Nodes are usually discrete, non-tender, less than 3 cm in diameter, and non-suppurative.
- In patients with chorioretinitis, ophthalmologic examination reveals yellow–white, cotton-like patches with indistinct margins of hyperemia. Lesions are usually multiple and develop distinct borders and black spots within the retina.
- Patients may have hepatomegaly.
DIAGNOSTIC TESTS & INTERPRETATION
Diagnosis is usually based on a compatible clinical picture, neuroimaging findings, and serology. Definitive diagnosis is based on pathology.
Lab
- T. gondii-specific IgG and IgM levels are part of the initial work up for toxoplasmosis and aid in determining whether infection is acute or a reactivation. However, approximately 20% of patients have no detectable antibodies, and the titer does not always rise during infection. Negative serology does not rule out infection, but a rising titer may be of diagnostic significance.
- Parasitemia may be detected in tissue culture in a proportion of patients with acute infection.
- Evaluation of other body fluids including bronchoalveolar lavage, cerebrospinal fluid (CSF), or amniotic fluid by direct examination (by Giemsa or immunofluorescence) can demonstrate tachyzoites.
- Polymerase chain reaction (PCR) of body fluids is possible but not often used because test performance varies greatly.
- CSF analysis usually reveals elevated protein and mild pleocytosis.
Imaging
- On neuroimaging, the abscesses of cerebral toxoplasmosis are typically multiple, located in the cortex or deep nuclei (thalamus and basal ganglia), surrounded by edema, and enhance in a ring-like pattern with contrast.
- Magnetic resonance imaging (MRI) has greater sensitivity than computed tomography (CT) for detection of smaller lesions in this population.
- After fetal infection, neuro-imaging reveals CNS calcifications and ventricular dilation.
Diagnostic Procedures/Other
- Definitive diagnosis of CNS toxoplasmosis requires brain biopsy or identification of the microorganism in CSF by Wright–Giemsa stain.
- Currently, brain biopsy is indicated for patients with focal enhancing cerebral lesions seen on CT and MRI who do not respond to a trial of empiric anti-toxoplasmosis therapy, for patients who are showing rapid clinical deterioration with neuroimaging, or for patients whose serology is not suggestive of toxoplasmosis.
- Chest X rays are abnormal in more than half of the patients with pulmonary toxoplasmosis.
DIFFERENTIAL DIAGNOSIS
- For immunocompetent patients with lymphadenopathy, the differential includes Epstein-Barr virus (EBV), cytomegalovirus (CMV), and acute HIV infection.
- For HIV-positive patients with CNS lesions, the differential includes lymphoma, cryptococcal and mycobacterial disease, bacterial abscess, and progressive multifocal leukoencephalopathy.
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MEDICATION
First Line
- Drugs, dosages, and treatment duration for extracerebral toxoplasmosis, such as ocular, pulmonary, or disseminated, are the same as for CNS involvement.
- The combination of pyrimethamine plus sulfadiazine is the regimen of choice for acute therapy.
- For acute therapy, the usual dose are:
- Sulfadiazine 1–1.5 g p.o. q.i.d.
- Pyrimethamine loading dose 200 mg p.o. × 1, followed by 75 mg p.o. per day.
- Folinic acid should always be co-administered with pyrimethamine to prevent the folinic acid deficiency and ameliorate the hematologic toxicity of pyrimethamine.
- Duration of treatment should be individualized, but it usually is for 6–8 weeks.
Second Line
ADDITIONAL TREATMENT
General Measures
For patients for whom there is a strong suspicion of cerebral toxoplasmosis, a trial of empiric therapy prior to definitive diagnosis is reasonable.
Additional Therapies
- For acute infection in pregnant women, spiramycin or a combination of sulfadiazine and pyrimethamine with leucovorin is used.
- For congenital toxoplasmosis, toxoplasmic meningitis with evidence of high intracranial pressures and chorioretinitis, steroids can be added until CSF protein normalizes, and impending herniation and/or vision-threatening inflammation resolves.
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FOLLOW-UP RECOMMENDATIONS
After induction treatment, HIV-infected patients should receive suppression therapy with pyrimethamine (25–50 mg p.o. per day) and sulfadiazine (500–1000 g p.o. per day) until CD4 T-cell count is greater than 200 cells/mm3 for 6 months.
Patient Monitoring
- Careful ophthalmologic examination is essential for newborns with suspected congenital infection.
- Patients with CNS disease should be carefully monitored for improvement with serial exams and imaging.
- Additionally, patients should be monitored for adverse effects of the medications (pyrimethamine causes rash and bone marrow suppression; sulfadiazine causes rash, GI disturbances, leukopenia, hepatitis and renal failure).
PATIENT EDUCATION
Pregnant patients and seronegative HIV-positive patients should be educated by their doctors regarding prevention of primary disease.
PROGNOSIS
80–90% of patients with AIDS will have a radiographic and/or clinical response within 7–10 days. If patients do not improve, brain biopsy should be pursued. Relapses of ocular toxoplasmosis occur in up to one-third of patients.
COMPLICATIONS
Ocular toxoplasmosis can lead to loss of central vision, nystagmus, or strabismus.
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ICD9
130.9 Toxoplasmosis, unspecified