Toxoplasmosis is infection with Toxoplasma gondii. Symptoms range from none to benign lymphadenopathy, a mononucleosis-like illness, to life-threatening central nervous system (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, histopathology, or polymerase chain reaction (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 11% of residents ≥ 6 years in the US are seropositive, which indicates that they have been infected, and more than 60% of some populations in other regions have been infected (see Centers for Disease Control and Prevention: Epidemiology & Risk Factors). The risk of developing serious disease is very low except for a fetus infected in utero and people who are or become severely immunocompromised with AIDS or other diseases.
Pathophysiology of Toxoplasmosis
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, eyes, 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 життєвий цикл
The only known definitive hosts for T. gondii are members of family Felidae (domestic cats and their relatives).
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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 causing disease, 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 were infected with Toxoplasma and developed immunity prior to pregnancy.
Transmission may occur via transfusion of whole blood or white blood cells or via transplantation of an organ from a seropositive donor.
In otherwise healthy people, congenital or acquired infection can reactivate in the eyes. Nonocular reactivation is very rare in healthy people. Past infection confers resistance to reinfection.
Symptoms and Signs of Toxoplasmosis
Infections may manifest in several ways:
Acute toxoplasmosis
Central nervous system (CNS) toxoplasmosis
Congenital toxoplasmosis
Ocular toxoplasmosis
Disseminated or non-CNS disease in immunocompromised patients
Гострий токсоплазмоз
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 and include lymphadenitis. Atypical lymphocytosis, mild anemia, leukopenia, and slightly elevated liver enzymes are common. The syndrome may persist for weeks but is almost always self-limited.
Токсоплазмоз ЦНС
Most patients with AIDS or other immunocompromised patients who develop toxoplasmosis present with encephalitis and ring-enhancing intracranial mass lesions seen on CT or MRI scans, both with contrast. Risk is greatest among those with CD4 counts of < 50/mcL; toxoplasmic encephalitis is rare when CD4 counts are > 200/mcL. 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.
Вроджений токсоплазмоз
Congenital toxoplasmosis 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. The severity of congenital diseases decreases if the mother becomes infected later in pregnancy.
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
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.
Очний токсоплазмоз
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.
Paul Whitten/SCIENCE PHOTO LIBRARY
Дисемінована інфекція та не ураження ЦНС
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 of Toxoplasmosis
Serologic testing
For central nervous system involvement, CT or MRI and lumbar puncture
Histopathologic evaluation of biopsies
Polymerase chain reaction–based assays of blood, cerebrospinal fluid, tissue, or, during pregnancy, amniotic fluid
Toxoplasmosis is usually diagnosed 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 weeks of acute illness, peak within 4 to 8 weeks, and eventually become undetectable, but they may be present for as long as 18 months after acute infection. IgG antibodies arise more slowly, peak in 1 to 2 months, and may remain high and stable for months to years. Assays for Toxoplasma IgM lack specificity.
Інтерпретація токсоплазма серологічні дослідження
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 | Chronic indeterminate |
Equivocal | Equivocal | Chronic indeterminate |
Equivocal | Positive | Possibly acute infection |
Positive | Negative | Infection for ≥ 6 months |
Positive | Equivocal | Infection for probably > 1 year or false-positive IgM result |
Positive | Positive | Possibly recent infection in the last 12 months or false-positive IgM result |
* Except in infants less than 12 months | ||
† If results are equivocal or interpretation is uncertain, testing additional samples at a reference laboratory or testing samples taken two weeks or more later may provide useful information. | ||
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 weeks 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 weeks 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, Toxoplasma Serology Laboratory, Palo Alto Research Institute, Palo Alto, CA). 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. Polymerase chain reaction (PCR) tests for parasite DNA in blood, cerebrospinal fluid (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 central nervous system (CNS) toxoplasmosis is suspected, patients should have head CT with contrast or MRI with contrast, or both plus a lumbar puncture if there are no signs of increased intracranial pressure. MRI is more sensitive than CT. MRI and CT with contrast 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 CNS toxoplasmosis is correct, clinical and radiographic improvement should become evident within 7 to 14 days. If symptoms worsen over the 1st week or do not lessen by the end of the 2nd week, 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 of Toxoplasmosis
Pyrimethamine and sulfadiazine plus leucovorin (to prevent bone marrow suppression); alternatively, the fixed drug combination trimethoprim-sulfamethoxazole in some situations
Clindamycin or atovaquone plus pyrimethamine when the patient is allergic to sulfonamides or does not tolerate sulfadiazine
Treatment of toxoplasmosis is not indicated for immunocompetent patients who are asymptomatic or have mild, uncomplicated acute infection; treatment is required only when visceral disease is present or symptoms are severe or persist.
However, specific treatment is indicated for acute toxoplasmosis in the following:
Neonates
Pregnant women with acute toxoplasmosis
Immunocompromised patients
Цінні поради та підводні камені
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Лікування імунокомпетентних пацієнтів
The most effective regimen in immunocompetent patients with visceral involvement or severe or persistent symptoms is pyrimethamine plus sulfadiazine, for 2 to 4 weeks. Dosage is
Pyrimethamine 50 mg twice a day for 2 days, then 25 to 50 mg once a day in adults (in children, 2 mg/kg orally on day 1, then 1 mg/kg once a day; maximum 25 mg/day) plus
Sulfadiazine 1 g orally 4 times a day in adults (in children, 50 mg/kg twice a day)
Folinic acid (leucovorin) is given concurrently to help protect against bone marrow suppression: adults 10 to 20 mg orally once a day (children 7.5 mg orally once a day)
In patients who have or develop sulfonamide hypersensitivity, clindamycin 600 to 800 mg orally 3 times a day is given with pyrimethamine and leucovorin instead of sulfonamides. Another option is atovaquone plus pyrimethamine and leucovorin. The fixed combination of trimethoprim with sulfamethoxazole has been used as an alternative as well as pyrimethamine and leucovorin plus clarithromycin, or dapsone, or azithromycin, but they have not been extensively studied.
Лікування хворих на СНІД або інші імунодефіцитні стани
It is important to optimize antiretroviral therapy.
Higher doses of pyrimethamine are used in immunocompromised patients, most of whom have AIDS with CNS toxoplasmosis or, uncommonly, involvement of other organs. A loading dose of pyrimethamine 200 mg orally is given the first day, then 50 mg once a day in patients < 60 kg and 75 mg once a day in those > 60 kg, plus sulfadiazine 1,000 mg orally 4 times a day in patients < 60 kg and 1,500 mg orally 4 times a day in patients > 60 kg for at least 6 weeks and 4 to 6 weeks after resolution of clinical signs and symptoms. Pyrimethamine bone marrow suppression can be minimized with leucovorin (also called folinic acid—not folate, which blocks the therapeutic effect). Dosage of leucovorin is 10 to 25 mg orally once a day (7.5 mg once a day in children). Even when leucovorin is given, the complete blood count should be monitored weekly.
If pyrimethamine is not available, trimethoprim-sulfamethoxazole, 5 mg/kg trimethoprim and 25 mg/kg sulfamethoxazole IV or orally twice a day is a potentially effective alternative, but pyrimethamine is more active than trimethoprim against the parasite's dihydrofolate reductase.
If patients cannot take sulfonamides, pyrimethamine and leucovorin plus clindamycin 600 mg 4 times a day can be used. Atovaquone 1,500 mg twice a day with or without pyrimethamine and leucovorin is another option.
Chronic maintenance therapy is used after successful treatment of acute disease to prevent relapses in patients who remain immunocompromised. Relapses are particularly common in AIDS patients with CD4 counts < 200/mcL. Maintenance therapy is continued until the CD4 counts remain > 200/mcL for > 6 months on antiretroviral therapy.
There are several options for maintenance therapy:
Sulfadiazine, pyrimethamine, and leucovorin
Clindamycin, pyrimethamine, and leucovorin
Atovaquone, pyrimethamine, and leucovorin
Atovaquone and sulfadiazine
Atovaquone
Sulfadiazine and pyrimethamine and leucovorin can be continued at lower doses than used for initial treatment: Sulfadiazine is given 1 g twice a day to 4 times a day with pyrimethamine 25 to 50 mg once a day and leucovorin 10 to 25 mg once a day. An alternative for patients who do not tolerate sulfonamides is clindamycin 600 mg 3 times a day plus pyrimethamine 25 to 50 mg once a day plus leucovorin 10 to 25 mg once a day, but an additional agent is needed to prevent pneumonia. If pyrimethamine is not available or not tolerated, trimethoprim-sulfamethoxazole 1 double strength tablet twice a day can be used for maintenance. Other options for chronic maintenance therapy include atovaquone 750 to 1,500 mg twice a day with pyrimethamine 25 mg once a day plus leucovorin 10 mg once a day; atovaquone 750 to 1,500 mg plus sulfadiazine 1 g twice a day to 4 times a day; or atovaquone alone 750 to 1,500 mg twice a day. The relapse rate may be higher with the atovaquone-based alternatives.
Лікування токсоплазмозу очей
Treatment of ocular toxoplasmosis is based on results of a complete ophthalmologic evaluation (degree of inflammation; visual acuity; size, location, and persistence of lesion). Doses are
Pyrimethamine 100 mg day 1 as a single loading dose, then 25 to 50 mg orally once a day in adults (in children, 2 mg/kg on day 1, then 1 mg/kg once a day) plus
Sulfadiazine 2 to 4 g orally day 1as a loading dose, then 500 mg to 1 g four times a day in adults (in children, 50 mg/kg twice a day) plus
Folinic acid (leucovorin) 5 to 25 mg orally once a day with each dose of pyrimethamine as long as pyrimethamine is given in adults (in children, 7.5 mg once a day)
The Centers for Disease Control and Prevention (CDC) recommends that therapy for ocular toxoplasmosis be continued for 4 to 6 weeks, followed by reevaluation of the patient's condition (see also CDC: Toxoplasmosis: Resources for Health Professionals).
Patients with ocular toxoplasmosis are also frequently given corticosteroids to reduce inflammation.
Лікування вагітних пацієнтів
Treatment of pregnant women with acute toxoplasmosis can decrease the incidence of fetal infection.
Spiramycin 1 g orally 3 or 4 times a day has been used safely to reduce transmission to the fetus in pregnant women with acute toxoplasmosis during the first 18 weeks of pregnancy, 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 18 weeks gestational age when amniotic fluid is obtained and tested using a polymerase chain reaction (PCR)–based assay. If no transmission has occurred, spiramycin can be continued to term. If the fetus is infected or a mother becomes infected after 18 weeks, pyrimethamine plus sulfadiazine plus leucovorin is used. Pyrimethamine is a potent teratogen and should not be used during the 1st and early 2nd trimester. NOTE: Spiramycin is not commercially available in the US, but is available through the U.S. Food and Drug Administration's Division of Anti-Infective Drug Products (phone: 301-796-1400).
Consultation with an infectious diseases expert is recommended.
Лікування немовлят з вродженим токсоплазмозом
Infants with congenital toxoplasmosis should be treated with pyrimethamine plus a sulfonamide for 1 year (1). Infants should also receive leucovorin while receiving pyrimethamine and for 1 week after pyrimethamine is stopped to prevent bone marrow suppression. Recommendations from the National Reference Laboratory for Toxoplasmosis (PAMF-TSL) and the Toxoplasmosis Center at the University of Chicago for treatment of congenitally infected infants are
Pyrimethamine 1 mg/kg orally twice a day for the first 2 days; then from day 3 to 2 months (or 6 months if symptomatic) 1 mg/kg once a day, then 1 mg/kg 3 times per week to complete 12 months of therapyplus
Sulfadiazine 50 mg/kg twice a day plus
Folinic acid (leucovorin) 10 mg 3 times a week
Довідковий матеріал щодо лікування
1. Maldonado YA, Read JS, Committee on Infectious Diseases: Diagnosis, treatment, and prevention of congenital toxoplasmosis in the United States. Pediatrics 139(2):e20163860, 2017. doi:10.1542/peds.2016-3860
Prevention of Toxoplasmosis
Washing hands thoroughly after handling raw meat, soil, or cat litter is essential to help prevent toxoplasmosis. Food possibly contaminated with cat feces should be avoided. Meat should be cooked to 165 to 170° F (73.9 to 76.7° C).
Pregnant women are advised to avoid contact with cats. If contact is unavoidable, pregnant women should at least avoid cleaning cat litter boxes or wear gloves when doing so. Gloves should also be worn while gardening to avoid contact with soil.
Primary chemoprophylaxis is recommended for patients with HIV and a positive IgG T. gondii serologic test once CD4 cell counts are < 100/mcL. Trimethoprim/sulfamethoxazole one double-strength tablet once a day, which also is prophylactic against Pneumocystis jirovecii, is typically used. If this dosage is not tolerated, alternatives are one double-strength tablet 3 times a week or one single-strength tablet once a day. Alternatives for patients who cannot tolerate trimethoprim/sulfamethoxazole at all include dapsone 50 mg once a day plus pyrimethamine 50 mg once a week and leucovorin 25 mg once a week; or dapsone 200 mg once a week plus pyrimethamine 75 mg once a week plus leucovorin 25 mg once a week. Chemoprophylaxis is continued until the CD4 cell count is > 200/mcL.
Ключові моменти
T. gondii reproduces sexually in the intestinal tract of cats; most human 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 11% of the US population have been infected with T. gondii, but symptomatic disease is rare and occurs mainly in fetuses who are infected when the mother acquires acute infection during pregnancy and transmits the infection transplacentally or in people who are immunocompromised by HIV or other causes.
Acute infection is usually asymptomatic in immunocompetent patients, but 10 to 20% have manifestations, similar to those of mononucleosis, including lymphadenopathy.
Immunocompromised patients typically present with encephalitis and have ring-enhancing intracranial mass lesions, seen on MRI or CT with contrast.
To diagnose, use serologic tests (for IgG and IgM antibodies), histopathology, or polymerase chain reaction.
Treatment is indicated mainly for congenitally infected neonates, pregnant women with acute infection, and immunocompromised patients.
Use pyrimethamine and sulfadiazine plus leucovorin or, if the patient is allergic to sulfonamides or sulfadiazine is not tolerated, pyrimethamine and clindamycin.
Pyrimethamine is a potent teratogen and should not be used during the 1st and early 2nd trimester of pregnancy; spiramycin is recommended then for maternal infection.
Antiretroviral therapy should be optimized in patients with AIDS; suppressive treatment is continued until patients are asymptomatic and CD4 cell counts are > 200/mcL for > 6 months.
Додаткова інформація
The following English-language resources may be useful. Please note that THE MANUAL is not responsible for the content of these resources.
Centers for Disease Control and Prevention (CDC): Resources for Health Professionals: Toxoplasmosis
AIDSinfo: Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents
