Toxoplasmosis
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Toxoplasmosis
• Toxoplasma gondii, an obligate intracellular protozoan, is acquired perorally, transplacentally, or, rarely, parenterally in laboratory accidents; by transfusion; or from a transplanted organ • T. gondii is a coccidian protozoan that multiplies only in living cells. The tachyzoites are oval or crescent-like, measuring 2–4 × 4–7 μm. Tissue cysts, which are 10–100 μm in diameter, may contain thousands of parasites and remain in tissues, especially the CNS and skeletal and heart muscle, for the life of the host. Toxoplasma can multiply in all tissues of mammals and birds.
• Newly infected cats excrete infectious Toxoplasma oocysts in their feces. Toxoplasma organisms are transmitted to cats by ingestion of infected meat containing encysted bradyzoites or by ingestion of oocysts excreted by other recently infected cats. The parasites then multiply through schizogonic and gametogonic cycles in the distal ileal epithelium of the cat intestine. Oocysts containing 2 sporocysts are excreted, and, under proper conditions of temperature and moisture, each sporocyst matures into 4 sporozoites. For about 2 wk the cat excretes 105–107 oocysts/day, which, in a suitable environment, may retain their viability for >1 yr. Oocysts sporulate 1–5 days after excretion and are then infectious. • Oocysts are killed by drying or boiling, but not exposure to bleach., Oocysts and tissue cysts are sources of animal and human infections
Human infection is usually acquired orally by eating undercooked or raw meat that contains cysts or food or other material contaminated with oocysts from acutely infected cats. Freezing meat to -20°C or heating it to 66°C renders the cysts noninfectious.. Toxoplasma organisms are not transmitted from person to person except for transplacental infection from mother to fetus and, rarely, by organ transplantation or transfusion.
Congenital Toxoplasmosis
Transmission to the fetus usually follows acquisition of infection by an immunologically normal mother during gestation. Congenital transmission from mothers infected before pregnancy is extremely rare except for immunocompromised women who are chronically infected. The incidence of infection among pregnant women depends on the general risk for infection in the specific locale and the proportion of the population that has not been infected previously.
PATHOGENESIS
When a mother acquires infection during gestation, organisms may disseminate hematogenously to the placenta. Of untreated maternal infections acquired in the 1st trimester, approximately 17% of fetuses are infected, usually with severe disease. Of untreated maternal infection acquired in the 3rd trimester, approximately 65% of fetuses are infected, usually with disease that is mild or inapparent at birth. These different rates of transmission and outcomes are most likely related to placental blood flow, virulence, inoculum of T. gondii, and immunologic capacity of the mother to limit parasitemia. Examination of the placenta of infected newborns may reveal chronic inflammation and cysts. Tachyzoites can be seen with Wright or Giemsa stains but are best demonstrated with immunoperoxidase technique. Tissue cysts stain well with periodic acid-Schiff and silver stains as well as with the immunoperoxidase technique. Gross or microscopic areas of necrosis may be present in many tissues, especially the CNS, choroid and retina, heart, lungs, skeletal muscle, liver, and spleen. Areas of calcification occur in the brain.
CLINICAL MANIFESTATIONS
Congenital toxoplasmosis usually occurs when a woman acquires primary infection while pregnant. Most often, maternal infection is asymptomatic or without specific symptoms or signs. As with other adults with acute toxoplasmosis, lymphadenopathy is the most common symptom, but this is present in only a small subset of mothers Congenital infection may present as a mild or severe neonatal disease, with onset during the 1st mo of life or with sequelae or relapse of a previously undiagnosed, and untreated, infection presenting during infancy or even later in life. There is a wide variety of manifestations of congenital infection ranging from hydrops fetalis and perinatal death to small size for gestational age, prematurity, peripheral retinal scars, persistent jaundice, mild thrombocytopenia, CSF pleocytosis, and the characteristic triad of chorioretinitis, hydrocephalus, and cerebral calcifications. Neurologic signs such as convulsions, setting-sun sign with downward gaze, and hydrocephalus with increased head circumference may be associated with or without substantial cerebral damage, or with relatively mild inflammation obstructing the aqueduct of Sylvius. If affected infants are treated promptly, signs and symptoms may resolve and they may develop normally.
Diagnosis
General and Pregnant Women
Because toxoplasmosis can only rarely be documented by the observation of parasites in patient specimens, antibody detection tests are the main source of diagnostic information. More commonly available tests include enzyme immunoassays (EIAs), agglutination tests, and indirect fluorescent antibody (IFA) tests. Positive immunoglobulin (Ig) G antibody tests are indicative of an infection occurring in the past, whereas positive IgM antibody tests indicate an infection occurring more recently. However, some IgM antibody tests can stay positive for 18 months or more, or give false-positive reactions. When clinicians are attempting to determine whether or not T. gondii infection occurred in a woman during her pregnancy, a serologic profile done in a reference laboratory—including the avidity test, differential agglutination, Sabin-Feldman dye test, IgM EIA, IgA EIA, and IgE EIA, and, if indicated, repeat titers—is helpful in attempting to determine the timing of infection. Serologic diagnosis must be confirmed at a reference laboratory before potentially toxic drugs or amniocentesis for T. gondii infection diagnosis are considered for a pregnant woman. When serologic test results indicate a potential T. gondii infection during pregnancy, diagnosis of congenital toxoplasmosis in the fetus is usually accomplished by amniocentesis and DNA polymerase chain reaction (PCR) testing of amniotic fluid at a reference laboratory from 18 weeks of gestation onward.
Infants
In the newborn, diagnosis of Toxoplasma infection is made with a combination of serologic testing (IgG, IgM, and IgA antibodies), parasite isolation, and evaluation of cerebrospinal fluid (CSF) (glucose, protein, cells, total IgG antibody, Toxoplasma-specific IgG and IgM antibodies, and direct examination for tachyzoites). In addition, an infant suspected of having congenital toxoplasmosis should have a thorough general, neurologic, and ophthalmologic examination and a CT scan of the head. Positive Toxoplasma-specific IgM or IgA is diagnostic of congenital infection. Although occasionally placental leak can lead to a false-positive IgM test in the infant, repeat testing in approximately 10 days can help resolve the diagnosis because the half-life of IgM is only 3 to 5 days. Maternal IgG antibodies in the newborn's peripheral blood reflect infection in the mother; however, persistent or increasing IgG antibody levels in the infant compared with the mother measured by the dye test or IFA test provide strong evidence of congenital infection. Persistence of a positive IgG test result in the infant beyond 1 year of life confirms congenital infection, whereas a negative IgG test at 1 or more years of age essentially rules out congenital infection. Demonstration of serum antibodies in the newborn that are directed against unique Toxoplasma epitopes on immunoblot that are not found in the mother provides diagnostic evidence for congenital infection. In addition, direct demonstration of the parasite by isolation (mouse inoculation or tissue culture) and amplification of T. gondii–specific DNA (e.g., PCR of CSF, peripheral blood, or urine) are used to diagnose infection in infants. Infants born to women who have serologic evidence of infections with human immunodeficiency virus (HIV) and Toxoplasma should be evaluated for congenital toxoplasmosis.
TREATMENT
Pyrimethamine plus sulfadiazine act synergistically against Toxoplasma, and combination therapy is indicated for many of the forms of toxoplasmosis. However, use of pyrimethamine is contraindicated during the 1st trimester of pregnancy. Spiramycin should be used to attempt to prevent vertical transmission of infection to the fetus of acutely infected pregnant women, and to treat congenital toxoplasmosis. Pyrimethamine inhibits the enzyme dihydrofolate reductase (DHFR), and thus the synthesis of folic acid, and therefore produces a dose-related, reversible, and usually gradual depression of the bone marrow, resulting in thrombocytopenia, leukopenia, and anemia. Reversible neutropenia is the most common adverse effect in treated infants. All patients treated with pyrimethamine should have platelet and leukocyte counts twice weekly. Seizures may occur with overdosage of pyrimethamine. Folinic acid, as calcium leukovorin, should always be administered concomitantly and for 1 wk after treatment with pyrimethamine is discontinued to prevent bone marrow suppression. Potential toxic effects of sulfonamides (e.g., crystalluria, hematuria, and rash) should be monitored. Hypersensitivity reactions occur, especially in patients with AIDS.
Congenital Toxoplasmosis
All newborns infected with T. gondii should be treated whether or not they have clinical manifestations of the infection because treatment may be effective in interrupting acute disease that damages vital organs. Infants should be treated for 1 yr with pyrimethamine (2 mg/kg/day for 2 days, then 1 mg/kg/day for 2 or 6 mo, then 1 mg/kg given on Monday, Wednesday, and Friday, or more often, PO), sulfadiazine (100 mg/kg/day divided bid PO), and leukovorin (5–10 mg given on Monday, Wednesday, and Friday, PO). Pyrimethamine and sulfadiazine are available only in tablet form and can be prepared as suspensions. Prednisone (1 mg/kg/day divided bid PO) has been utilized in addition when active chorioretinitis involves the macula or otherwise threatens vision or the CSF protein is >1,000 mg/dL at birth, but the efficacy is not established.
.Pregnant Women with T .gondii Infection
The immunologically normal pregnant woman who acquired T. gondii before conception does not need treatment to prevent congenital infection of her fetus. Treatment of a pregnant woman who acquires infection at any time during pregnancy reduces the chance of congenital infection in her infant. Spiramycin (1 g every 8 hr PO without food) is recommended for prevention of fetal infection if the mother develops acute Toxoplasmosis during pregnancy. Adverse reactions are infrequent and include paresthesias, rash, nausea, vomiting, and diarrhea. Pyrimethamine (50 mg once daily PO), sulfadiazine (2 g bid PO), and leukovorin (10 mg once daily PO) are recommended for confirmed or probable fetal infection except in the 1st trimester, when spiramycin is recommended because pyrimethamine is potentially teratogenic. Delay in maternal treatment during gestation results in greater brain and eye disease in the infant. Diagnostic amniocentesis should be performed at >17–18 wk of gestation in pregnancies when there is high suspicion of fetal infection. Chronically infected pregnant women who are immunocompromised have transmitted T. gondii to their fetuses. Such women should be treated with spiramycin throughout gestation.
PREVENTION
Counseling pregnant women about the methods of preventing transmission of T. gondii during pregnancy can substantially reduce acquisition of infection during gestation. Women who do not have specific antibody to T. gondii before pregnancy should only eat well-cooked meat during pregnancy and avoid contact with oocysts excreted by cats. Cats that are kept indoors, maintained on prepared food, and not fed fresh, uncooked meat should not contact encysted T. gondii or shed oocysts. Serologic screening, ultrasound monitoring, and treatment of pregnant women during gestation can also reduce the incidence and manifestations of congenital toxoplasmosis. No protective vaccine is available.
• Toxoplasma gondii, an obligate intracellular protozoan, is acquired perorally, transplacentally, or, rarely, parenterally in laboratory accidents; by transfusion; or from a transplanted organ • T. gondii is a coccidian protozoan that multiplies only in living cells. The tachyzoites are oval or crescent-like, measuring 2–4 × 4–7 μm. Tissue cysts, which are 10–100 μm in diameter, may contain thousands of parasites and remain in tissues, especially the CNS and skeletal and heart muscle, for the life of the host. Toxoplasma can multiply in all tissues of mammals and birds.
• Newly infected cats excrete infectious Toxoplasma oocysts in their feces. Toxoplasma organisms are transmitted to cats by ingestion of infected meat containing encysted bradyzoites or by ingestion of oocysts excreted by other recently infected cats. The parasites then multiply through schizogonic and gametogonic cycles in the distal ileal epithelium of the cat intestine. Oocysts containing 2 sporocysts are excreted, and, under proper conditions of temperature and moisture, each sporocyst matures into 4 sporozoites. For about 2 wk the cat excretes 105–107 oocysts/day, which, in a suitable environment, may retain their viability for >1 yr. Oocysts sporulate 1–5 days after excretion and are then infectious. • Oocysts are killed by drying or boiling, but not exposure to bleach., Oocysts and tissue cysts are sources of animal and human infections
Human infection is usually acquired orally by eating undercooked or raw meat that contains cysts or food or other material contaminated with oocysts from acutely infected cats. Freezing meat to -20°C or heating it to 66°C renders the cysts noninfectious.. Toxoplasma organisms are not transmitted from person to person except for transplacental infection from mother to fetus and, rarely, by organ transplantation or transfusion.
Congenital Toxoplasmosis
Transmission to the fetus usually follows acquisition of infection by an immunologically normal mother during gestation. Congenital transmission from mothers infected before pregnancy is extremely rare except for immunocompromised women who are chronically infected. The incidence of infection among pregnant women depends on the general risk for infection in the specific locale and the proportion of the population that has not been infected previously.
PATHOGENESIS
When a mother acquires infection during gestation, organisms may disseminate hematogenously to the placenta. Of untreated maternal infections acquired in the 1st trimester, approximately 17% of fetuses are infected, usually with severe disease. Of untreated maternal infection acquired in the 3rd trimester, approximately 65% of fetuses are infected, usually with disease that is mild or inapparent at birth. These different rates of transmission and outcomes are most likely related to placental blood flow, virulence, inoculum of T. gondii, and immunologic capacity of the mother to limit parasitemia. Examination of the placenta of infected newborns may reveal chronic inflammation and cysts. Tachyzoites can be seen with Wright or Giemsa stains but are best demonstrated with immunoperoxidase technique. Tissue cysts stain well with periodic acid-Schiff and silver stains as well as with the immunoperoxidase technique. Gross or microscopic areas of necrosis may be present in many tissues, especially the CNS, choroid and retina, heart, lungs, skeletal muscle, liver, and spleen. Areas of calcification occur in the brain.
CLINICAL MANIFESTATIONS
Congenital toxoplasmosis usually occurs when a woman acquires primary infection while pregnant. Most often, maternal infection is asymptomatic or without specific symptoms or signs. As with other adults with acute toxoplasmosis, lymphadenopathy is the most common symptom, but this is present in only a small subset of mothers Congenital infection may present as a mild or severe neonatal disease, with onset during the 1st mo of life or with sequelae or relapse of a previously undiagnosed, and untreated, infection presenting during infancy or even later in life. There is a wide variety of manifestations of congenital infection ranging from hydrops fetalis and perinatal death to small size for gestational age, prematurity, peripheral retinal scars, persistent jaundice, mild thrombocytopenia, CSF pleocytosis, and the characteristic triad of chorioretinitis, hydrocephalus, and cerebral calcifications. Neurologic signs such as convulsions, setting-sun sign with downward gaze, and hydrocephalus with increased head circumference may be associated with or without substantial cerebral damage, or with relatively mild inflammation obstructing the aqueduct of Sylvius. If affected infants are treated promptly, signs and symptoms may resolve and they may develop normally.
Diagnosis
General and Pregnant Women
Because toxoplasmosis can only rarely be documented by the observation of parasites in patient specimens, antibody detection tests are the main source of diagnostic information. More commonly available tests include enzyme immunoassays (EIAs), agglutination tests, and indirect fluorescent antibody (IFA) tests. Positive immunoglobulin (Ig) G antibody tests are indicative of an infection occurring in the past, whereas positive IgM antibody tests indicate an infection occurring more recently. However, some IgM antibody tests can stay positive for 18 months or more, or give false-positive reactions. When clinicians are attempting to determine whether or not T. gondii infection occurred in a woman during her pregnancy, a serologic profile done in a reference laboratory—including the avidity test, differential agglutination, Sabin-Feldman dye test, IgM EIA, IgA EIA, and IgE EIA, and, if indicated, repeat titers—is helpful in attempting to determine the timing of infection. Serologic diagnosis must be confirmed at a reference laboratory before potentially toxic drugs or amniocentesis for T. gondii infection diagnosis are considered for a pregnant woman. When serologic test results indicate a potential T. gondii infection during pregnancy, diagnosis of congenital toxoplasmosis in the fetus is usually accomplished by amniocentesis and DNA polymerase chain reaction (PCR) testing of amniotic fluid at a reference laboratory from 18 weeks of gestation onward.
Infants
In the newborn, diagnosis of Toxoplasma infection is made with a combination of serologic testing (IgG, IgM, and IgA antibodies), parasite isolation, and evaluation of cerebrospinal fluid (CSF) (glucose, protein, cells, total IgG antibody, Toxoplasma-specific IgG and IgM antibodies, and direct examination for tachyzoites). In addition, an infant suspected of having congenital toxoplasmosis should have a thorough general, neurologic, and ophthalmologic examination and a CT scan of the head. Positive Toxoplasma-specific IgM or IgA is diagnostic of congenital infection. Although occasionally placental leak can lead to a false-positive IgM test in the infant, repeat testing in approximately 10 days can help resolve the diagnosis because the half-life of IgM is only 3 to 5 days. Maternal IgG antibodies in the newborn's peripheral blood reflect infection in the mother; however, persistent or increasing IgG antibody levels in the infant compared with the mother measured by the dye test or IFA test provide strong evidence of congenital infection. Persistence of a positive IgG test result in the infant beyond 1 year of life confirms congenital infection, whereas a negative IgG test at 1 or more years of age essentially rules out congenital infection. Demonstration of serum antibodies in the newborn that are directed against unique Toxoplasma epitopes on immunoblot that are not found in the mother provides diagnostic evidence for congenital infection. In addition, direct demonstration of the parasite by isolation (mouse inoculation or tissue culture) and amplification of T. gondii–specific DNA (e.g., PCR of CSF, peripheral blood, or urine) are used to diagnose infection in infants. Infants born to women who have serologic evidence of infections with human immunodeficiency virus (HIV) and Toxoplasma should be evaluated for congenital toxoplasmosis.
TREATMENT
Pyrimethamine plus sulfadiazine act synergistically against Toxoplasma, and combination therapy is indicated for many of the forms of toxoplasmosis. However, use of pyrimethamine is contraindicated during the 1st trimester of pregnancy. Spiramycin should be used to attempt to prevent vertical transmission of infection to the fetus of acutely infected pregnant women, and to treat congenital toxoplasmosis. Pyrimethamine inhibits the enzyme dihydrofolate reductase (DHFR), and thus the synthesis of folic acid, and therefore produces a dose-related, reversible, and usually gradual depression of the bone marrow, resulting in thrombocytopenia, leukopenia, and anemia. Reversible neutropenia is the most common adverse effect in treated infants. All patients treated with pyrimethamine should have platelet and leukocyte counts twice weekly. Seizures may occur with overdosage of pyrimethamine. Folinic acid, as calcium leukovorin, should always be administered concomitantly and for 1 wk after treatment with pyrimethamine is discontinued to prevent bone marrow suppression. Potential toxic effects of sulfonamides (e.g., crystalluria, hematuria, and rash) should be monitored. Hypersensitivity reactions occur, especially in patients with AIDS.
Congenital Toxoplasmosis
All newborns infected with T. gondii should be treated whether or not they have clinical manifestations of the infection because treatment may be effective in interrupting acute disease that damages vital organs. Infants should be treated for 1 yr with pyrimethamine (2 mg/kg/day for 2 days, then 1 mg/kg/day for 2 or 6 mo, then 1 mg/kg given on Monday, Wednesday, and Friday, or more often, PO), sulfadiazine (100 mg/kg/day divided bid PO), and leukovorin (5–10 mg given on Monday, Wednesday, and Friday, PO). Pyrimethamine and sulfadiazine are available only in tablet form and can be prepared as suspensions. Prednisone (1 mg/kg/day divided bid PO) has been utilized in addition when active chorioretinitis involves the macula or otherwise threatens vision or the CSF protein is >1,000 mg/dL at birth, but the efficacy is not established.
.Pregnant Women with T .gondii Infection
The immunologically normal pregnant woman who acquired T. gondii before conception does not need treatment to prevent congenital infection of her fetus. Treatment of a pregnant woman who acquires infection at any time during pregnancy reduces the chance of congenital infection in her infant. Spiramycin (1 g every 8 hr PO without food) is recommended for prevention of fetal infection if the mother develops acute Toxoplasmosis during pregnancy. Adverse reactions are infrequent and include paresthesias, rash, nausea, vomiting, and diarrhea. Pyrimethamine (50 mg once daily PO), sulfadiazine (2 g bid PO), and leukovorin (10 mg once daily PO) are recommended for confirmed or probable fetal infection except in the 1st trimester, when spiramycin is recommended because pyrimethamine is potentially teratogenic. Delay in maternal treatment during gestation results in greater brain and eye disease in the infant. Diagnostic amniocentesis should be performed at >17–18 wk of gestation in pregnancies when there is high suspicion of fetal infection. Chronically infected pregnant women who are immunocompromised have transmitted T. gondii to their fetuses. Such women should be treated with spiramycin throughout gestation.
PREVENTION
Counseling pregnant women about the methods of preventing transmission of T. gondii during pregnancy can substantially reduce acquisition of infection during gestation. Women who do not have specific antibody to T. gondii before pregnancy should only eat well-cooked meat during pregnancy and avoid contact with oocysts excreted by cats. Cats that are kept indoors, maintained on prepared food, and not fed fresh, uncooked meat should not contact encysted T. gondii or shed oocysts. Serologic screening, ultrasound monitoring, and treatment of pregnant women during gestation can also reduce the incidence and manifestations of congenital toxoplasmosis. No protective vaccine is available.
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