Daraprim

Toxoplasmosis is caused by the protozoan parasite Toxoplasma gondii. A recent serologic survey (1) conducted as part of the Third National Health and Nutrition Survey found that 23 percent of adolescents and adults and 15 percent of women of childbearing age in the United States show laboratory evidence of T. gondii infection. Although T. gondii infection in adults is usually asymptomatic or associated with self-limited symptoms (e.g., fever, malaise, lymphadenopathy), infection in a pregnant woman may cause serious health problems if the parasite is transmitted to the fetus.

Based on extrapolation of data from regional studies, (2-4) 400 to 4,000 cases of congenital toxoplasmosis occur in the United States each year. Congenital toxoplasmosis can have severe sequelae, including mental retardation, blindness, and epilepsy in infancy or much later in life.

Family physicians may be confronted with a number of issues regarding toxoplasmosis. Some of these issues are related to clinical presentation, laboratory testing, and prevention.

Toxoplasma gondii

LIFE CYCLE

The T. gondii life cycle has three stages: tachyzoite, bradyzoite, and sporozoite. (5) During the acute stage of T. gondii infection, tachyzoites invade and replicate within cells and are responsible for congenital infection. The tachyzoites invade all organs, especially the muscles (including the heart), liver, spleen, lymph nodes, and central nervous system (CNS). During latent infection, bradyzoites are present in tissue cysts. Sporozoites are found in environmentally resistant oocysts formed after the sexual stage of the life cycle.

Members of the Felidae family, including domestic and feral cats, are the definitive hosts for the sexual stage of T. gondii, which takes place in their intestinal mucosa. During acute infection, cats excrete unsporulated (i.e., noninfectious) oocysts in their feces. Depending on environmental conditions, the oocysts sporulate and become infectious after one day to several weeks. Under favorable conditions (i.e., in warm, moist soil), oocysts remain infectious for a year or more.

TRANSMISSION

T. gondii is transmitted to humans by three principal routes (Figure 1). (6) First, humans can acquire T. gondii by eating raw or inadequately cooked infected meat, especially pork, mutton, and wild game, (7) or uncooked foods that have come in contact with infected meat. Second, humans can inadvertently ingest oocysts that cats have passed in their feces, either from a litter box or from soil (e.g., soil from gardening, on unwashed fruits or vegetables, or in unfiltered water). Third, women can transmit the infection transplacentally to their unborn fetus. In adults, the incubation period for T. gondii infection ranges from 10 to 23 days after the ingestion of undercooked meat and from five to 20 days after the ingestion of oocysts from cat feces.

A report (8) from the Economic Research Service of the U.S. Department of Agriculture concluded that one half of toxoplasmosis cases in the United States are caused by eating contaminated meat. This conclusion is supported by the findings of a community-based epidemiologic study. (9)

Women infected with T. gondii before conception rarely transmit the parasite to their fetus, but those who become acutely infected or have reactivation of T. gondii during pregnancy (i.e., because of immunosuppression) can transmit the organism transplacentally. The risk of congenital disease is lowest (10 to 25 percent) when maternal infection occurs during the first trimester and highest (60 to 90 percent) when maternal infection occurs during the third trimester. (10,11) However, congenital disease is more severe when infection is acquired in the first trimester. (10) The overall risk of congenital infection from acute T. gondii infection during pregnancy ranges from approximately 20 to 50 percent. (10)

Immunosuppression resulting from human immunodeficiency virus (HIV) infection or therapies for malignancies, organ transplantation, and lymphoproliferative disorders can result in the reactivation of latent T. gondii infection. Reactivation most often involves the CNS, and symptoms may include those of meningoencephalitis or a mass lesion. Women with reactivated T. gondii infection can transmit the organism transplacentally. (10)

RISK FACTORS

Recent epidemiologic studies have identified the following risk factors for T. gondii infection: owning a cat, (12) cleaning a cat litter box, (13) eating raw or undercooked pork, mutton, lamb, beef, or minced-meat products, (12-14) gardening, (15) eating raw or unwashed vegetables or fruits, (12) eating raw vegetables outside the home, (12) having contact with soil, (14) washing kitchen knives infrequently, (13) having poor hand hygiene, (12) travelling outside of Europe, Canada, or the United States, (14) and drinking municipal water from a contaminated reservoir. (16)

It is important to note that recent epidemiologic studies have not shown cat ownership to be a consistent risk factor for T. gondii infection. The risk of infection is not related to owning a cat but to being exposed to feces from a cat that is shedding oocysts. When cats become infected with T. gondii, they generally shed oocysts only for a few weeks during their lifetime. Indoor cats that do not hunt and are not fed raw meat are unlikely to acquire T. gondii infection and therefore pose little risk. Furthermore, a study (17) of cats induced to shed oocysts found no oocysts on the cats' fur after they shed the oocysts. Therefore, the possibility of T. gondii transmission through touching a cat is considered to be minimal or nonexistent. (7)

Because cats often do not develop antibodies to T. gondii during the oocyst-shedding period, serologic testing does not provide useful information about the ability of a particular cat to transmit toxoplasmosis. (7) A cat that tests positive for T. gondii probably has shed oocysts previously and therefore may pose less of a risk than a serologically negative cat. Because cats can shed oocysts more than once, serologic testing is not helpful if a cat is seropositive to T. gondii antibody. Testing a cat's stool to determine human risk is also of little value, because cats shed oocysts for only a short period of time.

Toxoplasmosis in Pregnant Women

SCREENING

A practice bulletin from the American College of Obstetricians and Gynecologists on perinatal viral and parasitic infections recommends toxoplasmosis screening only in high-risk persons or those in whom routine ultrasound examination (or ultrasonography performed for other reasons) shows findings such as hydrocephalus, intracranial calcifications, microcephaly, fetal growth retardation, ascites, or hepatosplenomegaly. (18) [Evidence level C, consensus/expert guidelines] Screening tests may have equivocal or false-positive results that could lead to inappropriate treatment or the termination of pregnancy. (19,20)

Because of the low incidence of toxoplasmosis in the United States, some investigators (21) have determined that the risk to the fetus would be greater from routine screening than from no screening. However, women with HIV infection should be screened for toxoplasmosis because of the risk of T. gondii reactivation and toxoplasmic encephalitis. (18)

DIAGNOSTIC TESTS

When acute T. gondii infection is suspected in a pregnant woman, the diagnosis should be pursued. Toxoplasmosis usually is diagnosed on the basis of antibody detection. In acute infection, IgG and IgM antibody levels generally rise within one to two weeks of infection. (22)

The presence of elevated levels of T. gondii-specific IgG antibodies indicates that infection has occurred but does not distinguish between recent infection and infection acquired in the distant past. Detection of T. gondii-specific IgM antibodies has been used as an aid in determining the time of infection: a negative IgM test result with a positive IgG result usually indicates infection at least six months previously. However, the interpretation of T. gondii-specific IgM-positive results is complicated by the persistence of IgM antibodies up to 18 months after infection (5) and by false-positive reactions in commercial tests. (19) A guide for interpreting laboratory tests is provided in Table 1, (5) and an algorithm for T. gondii serologic testing in patients older than one year is presented in Figure 2. (5)

IgM-positive test results should be confirmed by a Toxoplasma reference laboratory. (19) The laboratory may also be able to narrow the time of infection through the use of specific tests (e.g., IgG avidity test) (23) or a serologic profile (e.g., Sabin-Feldman dye test, IgM enzyme-linked immunosorbent assay [ELISA], IgA ELISA, IgE ELISA, differential agglutination). (24)

When a pregnant woman is found to be infected with T. gondii, the next step is to determine whether the fetus is infected. Physicians most often use polymerase chain reaction (PCR) testing of amniotic fluid to diagnose congenital toxoplasmosis. PCR testing of amniotic fluid is safer and more sensitive than fetal blood sampling, (25) and it allows earlier confirmation of fetal infection. (26) However, false-positive and false-negative tests may occur with PCR tests. Because of the high likelihood of fetal damage, abortion may be considered if T. gondii infection is confirmed and infection is thought to have occurred before the 16th week of pregnancy or if the fetus shows evidence of hydrocephalus. (10)

TREATMENT

If the presence of acute T. gondii infection in a pregnant woman is confirmed, treatment with spiramycin (Rovamycine) can be initiated in an effort to prevent transmission to the fetus. If fetal infection is confirmed through amniocentesis, the woman may be switched to pyrimethamine (Daraprim) and sulfadiazine after the first trimester (27,28) or, according to some experts,10 after the 18th week of gestation. [Reference 27--Evidence level B, nonrandomized study] Folinic acid (leucovorin) is given with pyrimethamine and sulfadiazine to protect bone marrow from the suppressive effects of pyrimethamine.

Spiramycin is an investigational drug in the United States and can only be obtained through the manufacturer (Aventis Pharmaceuticals, Bridgewater, N.J.) with approval from the U.S. Food and Drug Administration. (28) Pyrimethamine generally is not recommended for use in pregnant women because it is a folic acid antagonist (pregnancy category C drug) and can cause bone marrow suppression in both mother and infant.

The treatment of acute T. gondii infection in pregnancy has not been evaluated in randomized prospective studies. Questions have been raised about the effectiveness of treatment in preventing congenital infection (29) or sequelae in infants. (30) Nevertheless, historical observational studies suggest that treatment is beneficial, and a recent multicenter observational study (31) found that treatment in pregnancy was associated with a reduction of sequelae in infants but not a reduction in maternal-fetal transmission. (31)

Congenital Toxoplasmosis

CLINICAL MANIFESTATIONS

The classic triad of signs suggestive of congenital toxoplasmosis includes chorioretinitis, hydrocephalus, and intracranial calcifications. However, other clinical manifestations also are associated with the disease (Table 2). Because clinical manifestations may be nonspecific, T. gondii infection must be considered in a large variety of presentations. (22) Congenital toxoplasmosis can mimic disease caused by organisms such as herpes simplex virus, cytomegalovirus, and rubella virus.

Premature infants with toxoplasmosis may develop CNS and ocular disease in the first three months of life. In contrast, T. gondii- infected full-term infants more often have milder disease, with hepatosplenomegaly and lymphadenopathy in the first two months of life. (22) Although most infants infected in utero are born with no obvious signs of toxoplasmosis on routine newborn examination, up to 80 percent develop learning or visual disabilities later in life. (32,33) With congenital infection, reduction of visual acuity and new eye lesions may occur through the third decade of life or even later. Ocular problems require a complete ophthalmologic evaluation.

TREATMENT

Pyrimethamine and sulfadiazine generally are used to treat infants with congenital toxoplasmosis. Infants treated with these drugs have been shown to have improved outcomes compared with untreated infants and children from studies in the past. (10,34) [Reference 34--Evidence level B, uncontrolled study] Drug therapy usually is continued for one year. Active and recurrent toxoplasmic eye disease also frequently responds to antiparasitic drugs, which may be given with steroids.

Prevention of Toxoplasmosis in Pregnant Women

Recommendations for the prevention of toxoplasmosis in pregnant women are presented in Table 3.35 In addition, pregnant women who travel abroad should avoid eating undercooked meat or drinking untreated water.

Programs that educate women of childbearing age about the prevention of toxoplasmosis have demonstrated some success in changing risk behaviors (36) and have been associated with a decrease in T. gondii seroconversion over time. (37) Finally, newborn screening for toxoplasmosis has been used in two states (Massachusetts and New Hampshire) in an attempt to identify and treat T. gondii-infected infants. (4)

The authors indicate that they do not have any conflicts of interest. Sources of funding: none reported.

REFERENCES

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(10.) Remington JS, McLeod R, Thulliez P, Desmonts G. Toxoplasmosis. In: Remington JS, Klein JO, eds. Infectious diseases of the fetus and newborn infant. 5th ed. Philadelphia: Saunders, 2001:205-346.

(11.) Dunn D, Wallon M, Peyron F, Petersen E, Peckham C, Gilbert R. Mother-to-child transmission of toxoplasmosis: risk estimates for clinical counselling. Lancet 1999;353:1829-33.

(12.) Baril L, Ancelle T, Goulet V, Thulliez P, Tirard-Fleury V, Carme B. Risk factors for Toxoplasma infection in pregnancy: a case-control study in France. Scand J Infect Dis 1999;31:305-9.

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(14.) Cook AJ, Gilbert RE, Buffolano W, Zufferey J, Petersen E, Jenum PA, et al. Sources of toxoplasma infection in pregnant women: European multicentre case-control study. European Research Network on Congenital Toxoplasmosis. BMJ 2000;321:142-7.

(15.) Weigel RM, Dubey JP, Dyer D, Siegel AM. Risk factors for infection with Toxoplasma gondii for residents and workers on swine farms in Illinois. Am J Trop Med Hyg 1999;60:793-8.

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(28.) Drugs for parasitic diseases. Medical Letter. Retrieved February 5, 2003, from www.medletter. com/freedocs/parasitic.pdf.

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(30.) Gilbert R, Dunn D, Wallon M, Hayde M, Prusa A, Lebech M, et al. Ecological comparison of the risks of mother-to-child transmission and clinical manifestations of congenital toxoplasmosis according to prenatal treatment protocol. Epidemiol Infect 2001;127:113-20.

(31.) Foulon W, Villena I, Stray-Pedersen B, Decoster A, Lappalainen M, Pinon JM, et al. Treatment of toxoplasmosis during pregnancy: a multicenter study of impact on fetal transmission and children's sequelae at age 1 year. Am J Obstet Gynecol 1999;180 (2 pt 1):410-5.

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(33.) Wilson CB, Remington JS, Stagno S, Reynolds DW. Development of adverse sequelae in children born with subclinical congenital Toxoplasma infection. Pediatrics 1980;66:767-74.

(34.) McAuley J, Boyer KM, Patel D, Mets M, Swisher C, Roizen N, et al. Early and longitudinal evaluations of treated infants and children and untreated historical patients with congenital toxoplasmosis: the Chicago Collaborative Treatment Trial. Clin Infect Dis 1994;18:38-72.

(35.) Preventing congenital toxoplasmosis. Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep 2000;49(RR-2):57-75.

(36.) Carter AO, Gelmon SB, Wells GA, Toepell AP. The effectiveness of a prenatal education programme for the prevention of congenital toxoplasmosis. Epidemiol Infect 1989;103:539-45.

(37.) Foulon W, Naessens A, Lauwers S, De Meuter F, Amy JJ. Impact of primary prevention on the incidence of toxoplasmosis during pregnancy. Obstet Gynecol 1988;72(3 pt 1):363-6.

JEFFREY JONES, M.D., M.P.H., is a medical epidemiologist in the Epidemiology Branch, Division of Parasitic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention (CDC), Atlanta. He received his medical degree from the University of California, Davis, School of Medicine and a master of public health degree from the University of California, Berkeley. Dr. Jones' current research focuses on the prevention and epidemiology of Toxoplasma gondii infections.

ADRIANA LOPEZ, M.H.S., is an epidemiologist in the Division of Parasitic Diseases at the CDC. She earned a master of health science degree from Johns Hopkins School of Hygiene and Public Health, Baltimore, Md.

MARIANNA WILSON, M.S., is a microbiologist and chief of the reference immunodiagnostic laboratory in the Division of Parasitic Diseases at the CDC. She has been involved with research and clinical aspects of the immunodiagnosis of parasitic diseases for 35 years.

Address correspondence to Jeffrey Jones, M.D., M.P.H., Mailstop F-22, Centers for Disease Control and Prevention, 4770 Buford Highway NE, Atlanta, GA 30341-3724 (e-mail: jlj1@cdc.gov). Reprints are not available from the authors.

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