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Toxoplasmosis

by Richard D. Pearson, MD

Toxoplasmosis is infection with Toxoplasma gondii. Symptoms range from none to benign lymphadenopathy (a mononucleosis-like illness) to life-threatening CNS disease or involvement of other organs in immunocompromised people. Encephalitis can develop in patients with AIDS and low CD4 counts. Retinochoroiditis, seizures, and intellectual disability occur in congenital infection. Diagnosis is by serologic tests, histology, or PCR. Treatment is most often with pyrimethamine plus either sulfadiazine or clindamycin. Corticosteroids are given concurrently for retinochoroiditis.

Human exposure to toxoplasmosis is common wherever cats are found; an estimated 15% of residents in the US are seropositive. The risk of developing disease is very low except for a fetus infected in utero and people who are or become immunocompromised.

Pathophysiology

T. gondii is ubiquitous in birds and mammals. This obligate intracellular parasite invades and multiplies asexually as tachyzoites within the cytoplasm of any nucleated cell (see Figure: Toxoplasma gondii life cycle.). When host immunity develops, multiplication of tachyzoites ceases and tissue cysts form; cysts persist in a dormant state for years, especially in brain and muscle. The dormant Toxoplasma forms within the cysts are called bradyzoites. Sexual reproduction of T. gondii occurs only in the intestinal tract of cats; the resultant oocysts passed in the feces remain infectious in moist soil for months.

Toxoplasma gondii life cycle.

The only known definitive hosts for T. gondii are members of family Felidae (domestic cats and their relatives).

  • 1a. Oocysts are shed in the cat’s feces. Large numbers are shed, but usually only for 1–2 wk. Oocysts take 1–5 days to become infective.

  • 1b. Cats become reinfected by ingesting sporulated oocysts.

  • 2. Soil, water, plant material, or cat litter becomes contaminated with oocysts. Intermediate hosts in nature (eg, birds, rodents, wild game, animals bred for human consumption) become infected after ingesting infected materials.

  • 3. Oocysts develop into tachyzoites shortly after ingestion.

  • 4. Tachyzoites spread throughout the body and form tissue cysts in neural and muscle tissue.

  • 5. Cats become infected after consuming intermediate hosts containing tissue cysts.

  • 6a. Humans can become infected by ingesting undercooked meat containing tissue cysts.

  • 6b. Humans can become infected by ingesting food or water contaminated with cat feces or other feces-contaminated materials (eg, soil) or contact with a pet cat’s litter.

  • 7. Rarely, human infection results from blood transfusion or organ transplantation.

  • 8. Rarely, transplacental transmission from mother to fetus occurs.

  • 9. In the human host, parasites form tissue cysts, most commonly in skeletal muscle, myocardium, the brain, and the eyes; these cysts may remain throughout the life of the host and can reactivate if the host becomes immunocompromised.

Infection can occur by

  • Ingestion of oocysts

  • Ingestion of tissue cysts

  • Transplacental transmission

  • Blood transfusion or organ transplantation

Ingestion of oocysts in food or water contaminated with cat feces is the most common mode of oral infection. Infection can also occur by eating raw or undercooked meat containing tissue cysts, most commonly lamb, pork, or rarely beef. After ingestion of oocysts or tissue cysts, tachyzoites are released and spread throughout the body. This acute infection is followed by the development of protective immune responses and the formation of tissue cysts in many organs. The cysts can reactivate, primarily in immunocompromised patients. Toxoplasmosis reactivates in 30 to 40% of AIDS patients who are not taking antibiotic prophylaxis, but the widespread use of trimethoprim/sulfamethoxazole for Pneumocystis prophylaxis has dramatically reduced the incidence.

Toxoplasmosis can be transmitted transplacentally if the mother becomes infected during pregnancy or if immunosuppression reactivates a prior infection. Transmission of Toxoplasma to a fetus is extraordinarily rare in immunocompetent mothers who have had toxoplasmosis earlier in life. Transmission may occur via transfusion of whole blood or WBCs or via transplantation of an organ from a seropositive donor. In otherwise healthy people, congenital or acquired infection can reactivate in the retina. Past infection confers resistance to reinfection.

Symptoms and Signs

Infections may manifest in several ways:

  • Acute toxoplasmosis

  • CNS toxoplasmosis

  • Congenital toxoplasmosis

  • Ocular toxoplasmosis

  • Disseminated or non-CNS disease in immunocompromised patients

Acute toxoplasmosis

Acute infection is usually asymptomatic, but 10 to 20% of patients develop bilateral, nontender cervical or axillary lymphadenopathy. A few of these also have a mild flu-like syndrome of fever, malaise, myalgia, hepatosplenomegaly, and less commonly, pharyngitis, which can mimic infectious mononucleosis. Atypical lymphocytosis, mild anemia, leukopenia, and slightly elevated liver enzymes are common. The syndrome may persist for weeks but is almost always self-limited.


CNS toxoplasmosis

Most patients with AIDS or other immunocompromised patients who develop toxoplasmosis present with encephalitis and ring-enhancing intracranial mass lesions. Risk is greatest among those with CD4 counts of < 50/μL; toxoplasmic encephalitis is rare when CD4 counts are > 200/μL. These patients typically have headache, altered mental status, seizures, coma, fever, and sometimes focal neurologic deficits, such as motor or sensory loss, cranial nerve palsies, visual abnormalities, and focal seizures.


Congenital toxoplasmosis

This type results from a primary, often asymptomatic infection acquired by the mother during pregnancy. Women infected before conception ordinarily do not transmit toxoplasmosis to the fetus unless the infection is reactivated during pregnancy by immunosuppression. Spontaneous abortion, stillbirth, or birth defects may occur. The percentage of surviving fetuses born with toxoplasmosis depends on when maternal infection is acquired; it increases from 15% during the 1st trimester to 30% during the 2nd to 60% during the 3rd.

Disease in neonates may be severe, particularly if acquired early in pregnancy; symptoms include jaundice, rash, hepatosplenomegaly, and the characteristic tetrad of abnormalities: bilateral retinochoroiditis, cerebral calcifications, hydrocephalus or microcephaly, and psychomotor retardation. Prognosis is poor.

Many children with less severe infections and most infants born to mothers infected during the 3rd trimester appear healthy at birth but are at high risk of seizures, intellectual disability, retinochoroiditis, or other symptoms developing months or even years later.


Ocular toxoplasmosis

This type usually results from congenital infection that is reactivated, often during the teens and 20s, but rarely, it occurs with acquired infections. Focal necrotizing retinitis and a secondary granulomatous inflammation of the choroid occur and may cause ocular pain, blurred vision, and sometimes blindness. Relapses are common.


Disseminated infection and non-CNS involvement

Disease outside the eye and CNS is much less common and occurs primarily in severely immunocompromised patients. They may present with pneumonitis, myocarditis, polymyositis, diffuse maculopapular rash, high fevers, chills, and prostration. In toxoplasmic pneumonitis, diffuse interstitial infiltrates may progress rapidly to consolidation and cause respiratory failure, whereas endarteritis may lead to infarction of small lung segments. Myocarditis, in which conduction defects are common but often asymptomatic, may rapidly lead to heart failure. Untreated disseminated infections are usually fatal.


Diagnosis

  • Serologic testing

  • For CNS involvement, CT or MRI and lumbar puncture

The diagnosis is usually made serologically using an indirect fluorescent antibody (IFA) test or enzyme immunoassay (EIA) for IgG and IgM antibodies (see Table: Interpretation of Toxoplasma Serologic Testing*). Specific IgM antibodies appear during the first 2 wk of acute illness, peak within 4 to 8 wk, and eventually become undetectable, but they may be present for as long as 18 mo after acute infection. IgG antibodies arise more slowly, peak in 1 to 2 mo, and may remain high and stable for months to years. Assays for toxoplasma IgM lack specificity.

Interpretation of Toxoplasma Serologic Testing*

IgG

IgM

Interpretation

Negative

Negative

No evidence of infection

Negative

Equivocal

Possibly early infection or false-positive IgM result

Negative

Positive

Possibly acute infection or false-positive IgM result

Equivocal

Negative

Indeterminate

Equivocal

Equivocal

Indeterminate

Equivocal

Positive

Possibly acute infection

Positive

Negative

Infection for > 1 yr

Positive

Equivocal

Infection for probably > 1 yr or false-positive IgM result

Positive

Positive

Possibly recent infection in the last 12 mo or false-positive IgM result

*Except in infants

Adapted from the Centers for Disease Control and Prevention (CDC): Toxoplasmosis: Antibody detection. Available at http://www.cdc.gov/dpdx/toxoplasmosis/dx.html ; last accessed January 24, 2014.

The diagnosis of acute toxoplasmosis during pregnancy and in the fetus or neonate can be difficult, and consultation with an expert is recommended. If the patient is pregnant and IgG and IgM are positive, an IgG avidity test should be done. High avidity antibodies in the first 12 to 16 wk of pregnancy essentially rules out an infection acquired during gestation. But a low IgG avidity result cannot be interpreted as indicating recent infection because some patients have persistent low IgG avidity for many months after infection. Suspected recent infection in a pregnant woman should be confirmed before intervention by having samples tested at a toxoplasmosis reference laboratory. If the patient has clinical illness compatible with toxoplasmosis but the IgG titer is low, a follow-up titer 2 to 3 wk later should show an increase in antibody titer if the illness is due to acute toxoplasmosis, unless the host is severely immunocompromised.

In general, detection of specific IgM antibody in neonates suggests congenital infection. Maternal IgG crosses the placenta, but IgM does not. Detection of Toxoplasma-specific IgA antibodies is more sensitive than IgM in congenitally infected infants, but it is available only at special reference facilities (eg, Palo Alto Medical Foundation [telephone 650-853-4828]). An expert should be consulted when fetal or congenital infection is suspected.

Toxoplasma are occasionally demonstrated histologically. Tachyzoites, which are present during acute infection, take up Giemsa or Wright stain but may be difficult to find in routine tissue sections. Tissue cysts do not distinguish acute from chronic infection. Toxoplasma must be distinguished from other intracellular organisms, such as Histoplasma, Trypanosoma cruzi, and Leishmania. PCR tests for parasite DNA in blood, CSF, or amniotic fluid are available at several reference laboratories. PCR-based analysis of amniotic fluid is the preferred method to diagnose toxoplasmosis during pregnancy.

If CNS toxoplasmosis is suspected, patients should have head MRI, CT with contrast agent, or both plus a lumbar puncture see Lumbar puncture (spinal tap) if there are no signs of increased intracranial pressure. MRI is more sensitive than CT. MRI and CT typically show single or multiple rounded, ring-enhancing lesions. Although these lesions are not pathognomonic, their presence in patients with AIDS and CNS symptoms warrants a trial of chemotherapy for T. gondii. CSF may be positive for lymphocytic pleocytosis, and the protein level may be elevated.

Acute infection should be suspected in immunocompromised patients if the IgG is positive. However, IgG antibody levels in AIDS patients with Toxoplasma encephalitis are usually low to moderate, and IgG antibodies are sometimes absent; IgM antibodies are not present.

If the suspected diagnosis of toxoplasmosis is correct, clinical and radiographic improvement should become evident within 7 to 14 days. If symptoms worsen over the 1st wk or do not lessen by the end of the 2nd wk, a brain biopsy should be considered.

Ocular disease is diagnosed based on the appearance of the lesions in the eye, symptoms, course of disease, and results of serologic testing.

Treatment

  • Pyrimethamine plus sulfadiazine (when treatment is indicated)

Most immunocompetent patients do not require therapy unless visceral disease is present or severe symptoms persist. However, specific treatment is indicated for acute toxoplasmosis in neonates, pregnant women, and immunocompromised patients.

The most effective regimen in immunocompetent patients is pyrimethamine plus sulfadiazine. Dosage for pyrimethamine is 100 mg on day 1, then 25 to 100 mg once/day for 2 to 4 wk in adults (2 mg/kg po for 2 days, then 1 mg/kg once/day in children; maximum 25 mg/day). Dosage for sulfadiazine is 1 to 1.5 g po qid for 2 to 4 wk in adults (25 to 50 mg/kg qid in children). Higher doses of pyrimethamine are used in HIV-infected patients with CNS toxoplasmosis. A loading dose of pyrimethamine 200 mg is given the first day, then 50 to 100 mg/day plus sulfadiazine for at least 6 wk. In patients who have or develop sulfonamide hypersensitivity, clindamycin 600 to 800 mg po tid is given with pyrimethamine instead of sulfonamides. Another option is atovaquone 1500 mg q 12 h plus pyrimethamine. Antiretroviral therapy should be optimized in patients with AIDS. Relapses of toxoplasmosis are common in patients with AIDS, and suppressive treatment should continue indefinitely unless the CD4 count increases and remains > 200/μL and patients remain symptom-free. Pyrimethamine bone marrow suppression can be minimized with leucovorin (also called folinic acid; not folate, which blocks the therapeutic effect), but the CBC should be monitored weekly. The dosage is 10 to 25 mg po once/day (7.5 mg in children). Patients with ocular toxoplasmosis are also given corticosteroids.

Treatment of pregnant women with primary infection can decrease the incidence of fetal infection. Spiramycin 1 g po tid or qid has been used safely to reduce transmission in pregnant women during the 1st trimester (available from the FDA [telephone 301-827-2335]), but spiramycin is less active than pyrimethamine plus sulfonamide and does not cross the placenta. Spiramycin is continued until fetal infection is documented or excluded at the end of the 1st trimester. If no transmission has occurred, spiramycin can be continued to term. If the fetus is infected, pyrimethamine plus sulfadiazine is used. Pyrimethamine is a potent teratogen and should not be used during the 1st trimester. Consultation with an infectious diseases expert is recommended.

Congenitally infected infants should be treated with pyrimethamine every 2 to 3 days and with sulfadiazine once/day for 1 yr. Infants should also receive leucovorin while receiving pyrimethamine and for 1 wk after pyrimethamine is stopped to prevent bone marrow suppression.

Prevention

Washing hands thoroughly after handling raw meat, soil, or cat litter is essential. Food possibly contaminated with cat feces should be avoided. Meat should be cooked to 165° to 170° F (73.9° to 76.7° C).

Chemoprophylaxis is recommended for patients with HIV and a positive IgG T. gondii serologic test once CD4+ cell counts are < 100/μL. One double-strength tablet of trimethoprim/sulfamethoxazole once/day, which also is prophylactic against Pneumocystis jirovecii, is recommended. One double-strength tablet 3 times/wk is an alternative. If patients cannot tolerate trimethoprim-sulfamethoxazole, dapsone plus pyrimethamine and leucovorin is recommended. Atovaquone with or without pyrimethamine and leucovorin can also be used. Chemoprophylaxis is continued until CD4+ cell counts are > 200/μL for ≥ 3 mo.

Key Points

  • T. gondii reproduces only in the intestinal tract of cats; most infections result from direct or indirect contact with cat feces but can be acquired transplacentally or by ingestion of poorly cooked meat that contains cysts.

  • About 15% of the US population had been infected, but symptomatic disease is rare and occurs mainly in fetuses infected in utero and in people who are immunocompromised.

  • Acute infection is usually asymptomatic, but 10 to 20% of patients have manifestations similar to those of mononucleosis.

  • Immunocompromised patients typically present with encephalitis and have ring-enhancing intracranial mass lesions, seen on MRI or CT.

  • To diagnose, use serologic tests (for IgG and IgM antibodies), histology, or PCR.

  • Treatment is indicated mainly for neonates, pregnant women, and immunocompromised patients; pyrimethamine plus sulfadiazine is used.

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