Current Diagnosis & Treatment in Infectious Diseases

Section VII - Parasitic Infections

81. Toxoplasma gondii

Jose G. Montoya MD

General Considerations

  • Epidemiology.Toxoplasma gondii infection, or toxoplasmosis, is a zoonosis (the definitive hosts are members of the cat family). The two most common routes of infection in humans are by oral ingestion of the parasite and by transplacental (congenital) transmission to the fetus. Ingestion of undercooked or raw meat that contains cysts or of water or food contaminated with oocysts results in acute infection.

In humans, the prevalence of toxoplasmosis increases with age. There are also considerable geographic differences in prevalence rates (eg, 10% in Palo Alto, CA; 15% in Boston, MA; 30% in Birmingham, AL; 70% in France; ≤ 90% in El Salvador). Differences in the epidemiology of T gondii infection in various geographic locales and between population groups within the same locale may be explained by differences in exposure to the organism. Occasionally, outbreaks occur within families or certain populations. The possibility of an outbreak should always be suspected with every case of recently acquired acute infection.

The incidence of congenital toxoplasmosis is directly correlated with three factors: (1) the prevalence of primary infection among women during pregnancy, (2) the gestational age at which a pregnant woman acquires the infection, and (3) the types of public health programs available for prevention, detection, and treatment of the infection during pregnancy. Although screening for Toxoplasma infection is compulsory during pregnancy in some countries such as Austria and France, routine serological screening is not performed in the United States. Without any therapeutic intervention, the incidence of congenital toxoplasmosis is ~ 15% for a fetus whose mother becomes infected during the first trimester, 30% during the second trimester, and 60% during the third trimester. Spiramycin decreases the incidence of fetal infection by ~ 60%. It has been reported that, if maternal infection is acquired during the first 2 weeks of gestation and spiramycin is administered for the entire pregnancy, the incidence of fetal infection is negligible.

As an opportunistic pathogen in HIV-infected persons, T gondii has had a major impact on public health. The incidence of toxoplasmosis in an HIV-infected population is directly correlated with four factors: (1) the prevalence of anti-Toxoplasma antibodies, (2) the degree of immunosuppression as estimated by the CD4 cell count, (3) the frequency with which effective prophylactic regimens against Toxoplasma reactivation are used, and (4) the frequency with which highly active antiretroviral therapy is used. Of individuals seropositive for both HIV and Toxoplasma with CD4 counts of < 100 cells/mm3, 30%–50% will develop toxoplasmic encephalitis (TE) if prophylaxis is not used. Genetic factors may also play a role in predisposition of AIDS patients for this disease, based on findings from a murine model of TE and the observation that not all HIV-infected patients with positive T gondii serology develop TE. Human lymphocyte antigen DQ3 appears to be a genetic marker of susceptibility to development of TE in AIDS patients, and DQ1 may be a marker of resistance.

Even before the emergence of AIDS, TE had been recognized as a major cause of morbidity and mortality among non–HIV-immunosuppressed patients, especially in those whose underlying disease or therapy caused a deficiency in T-cell–mediated immunity (eg, Hodgkin's disease and heart, lung, kidney, and bone marrow transplantation).

  • Microbiology.T gondii is an obligate intracellular coccidian protozoan that exists in three forms: the oocyst (which releases sporozoites), the tachyzoite, and the tissue cyst (which contains and may release bradyzoites). The parasite undergoes two cycles, an enteroepithelial sexual cycle in the small bowel of members of the cat family and an extraintestinal asexual cycle in cats as well as in all other infected animals, including humans. Cats shed oocysts after they ingest any of the three forms of the parasite. Humans usually become infected by ingestion of tissue cysts (in meat) or oocysts (in cat feces); the outer walls of both are disrupted by enzymatic degradation, and the parasites are liberated into the intestinal lumen. They become tachyzoites and spread to virtually all cells and tissues of the body.
  • Oocyst.Oocysts are formed in the small bowel of members of the cat family and are excreted in their feces for 7–20 days. They are highly resistant to conditions found within the external environment. As many as 10 million oocysts may be shed in a single day and will become infectious (by sporulation) in 1–21 days, depending on temperature and availability of oxygen.
  • Tachyzoite.Tachyzoites are crescent or oval shaped and measure 2–4 µm wide by 4–8 µm long. They require an intracellular habitat to survive and multiply despite having their own Golgi apparatus, ribosomes, and mitochondria. Tachyzoites penetrate host cells by an active process involving the components of an “apical complex” (hence the term apicomplexan). They reside and multiply within an intracellular parasitophorous vacuole whose composition (eg, acidity) is dictated in large part by the parasite. In the laboratory, tachyzoites are propagated in the peritoneum of mice and in tissue-cultured mammalian cells. The presence of tachyzoites in human fluids or tissues is the hallmark of acute infection.
  • Tissue cyst.After cell entry and replication of the tachyzoite form, encystation and formation of tissue cysts may occur. The precise conditions that promote cyst formation are not known. The tissue cyst is formed within a host cell and may vary in size from those containing only a few organisms (bradyzoites) to those ≥ 200 µm in diameter containing several thousand bradyzoites. Tissue cysts stain well with periodic acid-Schiff reagent, Wright-Giemsa, Gomori-methenamine silver, and immunoperoxidase stains. The cysts are spherical when found in the brain and conform to the shape of muscle fibers when in heart and skeletal muscle tissue. The most common sites of latent infection are the central nervous system (CNS); eye; and skeletal, smooth, and heart muscles. Because of this persistence in tissues, demonstration of cysts in histologic sections does not necessarily mean that the infection was recently acquired or that it is clinically relevant.
  • Stage conversion.Tachyzoites and bradyzoites differ phenotypically. Tachyzoites multiply rapidly and synchronously, forming rosettes, thereby lysing the cell, whereas the more slowly replicating bradyzoites form tissue cysts. Major differences in energy metabolism and in antigenic structure of tachyzoites and bradyzoites reflect the expression of stage-specific pathways and molecules that promote parasite survival in diverse environments and under diverse conditions within the host.
  • Pathogenesis.T gondii multiplies inside cells at the site of invasion (the gastrointestinal tract appears to be the major route for and the initial site of infection in nature). After host cell disruption, parasites invade adjacent cells from which they spread throughout the body via lymphatics and the bloodstream. Humoral immunity and cellular immunity appear to curtail successfully the parasitemic phase; only those parasites protected by an intracellular habitat or within tissue cysts survive. An effective immune response is also responsible for a significant early reduction in the number of T gondii in all tissues. Thereafter, tachyzoites are rarely demonstrated in tissues.

The tissue cyst form is responsible for residual infection and persists primarily in brain, skeletal, and heart muscle, and in the eye. Whereas toxoplasmosis in severely immunodeficient individuals may be caused by primary infection, it most often is the result of recrudescence of a latent infection.

The histopathologic changes of toxoplasmic lymphadenitis are frequently diagnostic in immunocompetent individuals. There is a characteristic triad of findings: a reactive follicular hyperplasia, irregular clusters of epithelioid histiocytes encroaching on and blurring the margins of the germinal centers, and focal distension of sinuses with monocytoid cells.

Ocular involvement in immunocompetent patients produces acute retinochoroiditis characterized by necrosis and severe inflammation. Granulomatous inflammation of the choroid is secondary to the necrotizing retinitis.

Involvement of the CNS is characterized by multiple enlarging foci of necrosis and microglial nodules. Necrosis is the most salient feature of the disease because of vascular involvement. The presence of multiple brain abscesses is the most typical feature of TE in severely immunodeficient patients and is particularly characteristic in patients with AIDS. At autopsy in most AIDS patients with TE, cerebral hemispheres are involved, with a peculiar predilection for the basal ganglia. Pulmonary toxoplasmosis in the immunodeficient patient may present as interstitial pneumonitis, necrotizing pneumonitis, consolidation, and/or pleural effusion. Chorioretinitis in AIDS patients is characterized by segmental panophthalmitis and areas of coagulative necrosis associated with tissue cysts and tachyzoites.

  • Immunity to T gondii.After disease in the immunocompetent host, immunity against T gondii is lifelong. Cellular immunity appears to be more important than humoral immunity in defense of the brain. A well-orchestrated interaction between CD4 and CD8 T lymphocytes; lymphokine-activated killer, natural killer, and γδ T cells; and cytokines such as interferon-γ, tumor necrosis factor-α, interleukin-1 (IL-1), IL-2, IL-4, IL-6, IL-7, IL-10, IL-12, and IL-15 appears to determine the outcome of the parasite-human host interaction. Nitric oxide may have a tissue-specific protective role.

Clinical Findings

Primary infection in any host often goes unrecognized. In ~ 10% of immunocompetent individuals, it causes a self-limited and nonspecific illness that rarely requires treatment. The most frequently observed clinical manifestation in this setting is lymphadenopathy and fatigue without fever; other manifestations include chorioretinitis, myocarditis, and polymyositis (Box 81-1). Reinfection occurs but does not appear to result in clinically apparent disease. In contrast to the usually benign course of the initial infection in immunologically intact hosts, the congenitally infected fetus and newborn and immunocompromised patients are at high risk for severe or life-threatening disease caused by this parasite. Congenital toxoplasmosis is the result of maternal infection acquired during gestation. Among immunologically impaired individuals, toxoplasmosis most often occurs in those with defects in T-cell–mediated immunity such as those with hematological malignancies, bone marrow and solid-organ transplants, or AIDS.

BOX 81-1 Clinical Syndromes Associated with Toxoplasmosis1




·  Asymptomatic

·  90% of acute infection goes unrecognized

·  Lymphadenitis

·  Regional or generalized lymphadenopathy

·  Chorioretinitis

·  Intensely white focal retinal lesions with overlying vitritis, with or without associated scars; may result from reactivation of congenital or postnatally acquired disease or from recently acquired acute disease

·  Myocarditis

·  Arrythmias, pericarditis, heart failure

·  Polymyositis

·  Patients with acute toxoplasmosis have developed polymyositis/dermatomyositis–like syndromes

·  Systemic

·  Low–grade fever, general malaise, headache, sore throat, myalgia

·  Disseminated disease is extremely rare; may present with fever, pneumonitis, hepatitis, or, possibly, encephalitis


·  Encephalitis

·  Focal or nonfocal neurological symptoms and/or mental status changes; usually occurs in the setting of advanced T–cell–mediated immunity impairment

·  Chorioretinitis

·  Can present atypically and/or with significant retinal necrosis

·  Myelopathy

·  Cervical, thoracic, or lumbar

·  Pneumonitis

·  Interstitial infiltrates

·  Systemic

·  Fever, multiorgan involvement, acute respiratory failure, and septic shocklike syndrome


·  Asymptomatic

·  90% of acute infection goes unrecognized

·  Lymphadenitis

·  Regional or generalized lymphadenopathy


·  Neurologic disease

·  Ultrasound may be normal or reveal ventricular dilatation, intracranial calcifications

·  Generalized disease

·  Ultrasound may be normal or reveal increased placental thickness, hepatomegaly, ascites


·  Asymptomatic

·  85% of newborns with congenital disease appear normal at birth

·  Neurologic disease

·  Seizures, chorioretinitis, abnormal neurological exam, hydrocephalus, cerebral calcifications

·  Generalized disease

·  Fever, hepatosplenomegaly, lymphadenopathy, jaundice, thrombocytopenia, anemia

1Syndromes are not mutually exclusive. Patients may present simultaneously or sequentially with two or more syndromes (ie, an otherwise immunocompetent patient may have lymphadenitis and chorioretinitis, or a newborn may present with hydrocephalus, cerebral calcifications, and thrombocytopenia).

  • Signs and symptoms.
  • Infection in immunocompetent adults and children.Primary infection with T gondii in children and adults is asymptomatic in the vast majority of cases. Lymphadenopathy and fatigue, without fever, are the most common manifestations in the minority that become symptomatic. The lymph nodes most commonly involved are cervical, suboccipital, supraclavicular, axillary, and inguinal. Lymphadenopathy is usually regional; often a single posterior cervical node is enlarged. On palpation, the nodes are discrete, nontender, and nonfluctuant. Occasionally, lymph nodes may become matted. Fever, sore throat, maculopapular rash, malaise, night sweats, myalgias, hepatosplenomegaly, or atypical lymphocytes are variably present. The clinical picture may resemble infectious mononucleosis or cytomegalovirus (CMV) infection; however, toxoplasmosis probably causes < 1% of mononucleosis-like syndromes. In rare cases, lymphadenopathy may persist for months.

Toxoplasmic chorioretinitis can occur either in the setting of acute acquired infection (sporadic and epidemic) or as a reactivation of intrauterine or postnatally acquired infection. Patients who present with chorioretinitis as a late sequela of intrauterine infection are more frequently in the second and third decades of life (it is rare after age 40); bilateral disease, retinal scars, and involvement of the macula are hallmarks of the retinal disease in these cases. In contrast, patients who present with toxoplasmic chorioretinitis in the setting of acute toxoplasmosis are more often in the fourth to sixth decades of life and most often have unilateral involvement. The eye lesions usually spare the macula and are not associated with old scars.

  • Infection in pregnant women.Recognition of toxoplasmosis in pregnancy is important only because of the risk of transmission to the fetus. This risk is limited almost exclusively to those fetuses whose mothers acquire the infection for the first time during gestation. Acquisition of Toxoplasmainfection before pregnancy in an otherwise healthy female does not pose a significant risk of transplacental transmission. On rare occasions, transmission to the fetus has occurred in immunocompetent women infected with T gondii within 3 months of conception. In immunocompromised women, such as those with HIV infection, acquisition of T gondii before conception (chronic infection) has then led to transmission to the fetus as a consequence of reactivation.
  • Congenital toxoplasmosis.Of newborns with congenital toxoplasmosis, ~ 85% appear normal at birth. Thus, one cannot rely on clinical examination alone to raise the possibility of this disease. However, if untreated, congenital toxoplasmosis will inevitably lead to disease in most infected children.

The earlier in gestation a mother is infected with T gondii, the more severe is the disease in the fetus and newborn, despite the lower frequency with which transmission occurs with shorter periods of gestation. Findings include chorioretinitis with blindness, epilepsy, psychomotor disorders and developmental delay, hearing loss, jaundice, rash, hematologic abnormalities, and pneumonitis. The classic triad of hydrocephalus, chorioretinitis, and cerebral calcifications is seen only rarely.

  • Infection in immunocompromised patients.In immunocompromised patients, toxoplasmosis almost always occurs as a result of reactivation of previously acquired infection. Toxoplasmosis may also result when a seronegative recipient receives a heart from a seropositive donor. In contrast to the relatively favorable course of toxoplasmosis in almost all immunocompetent individuals, it is a dreadful and often life-threatening disease in immunodeficient patients.

In this population, the brain is the most common affected organ. The clinical presentation of TE varies from a subacute, gradual process that evolves over weeks to an acute state of confusion, with or without focal neurologic deficits evolving over days. Clinical manifestations include alteration in mental status, seizures, motor weakness, cranial-nerve disturbances, sensory abnormalities, cerebellar signs, movement disorders, and neuropsychiatric findings. Constitutional symptoms and signs such as fever and malaise are variable.

The most common focal neurologic findings are hemiparesis and abnormalities of speech. Because T gondii causes predominantly encephalitis with little or no meningeal involvement, signs of meningeal irritation are rare. Cranial-nerve lesions develop secondary to brainstem involvement. Seizures, cerebral hemorrhage, and diffuse TE may present acutely and progress rapidly to death. Spinal-cord toxoplasmosis in AIDS patients can present with motor or sensory disturbances of single or multiple extremities, bladder dysfunction, and/or bowel dysfunction. Cervical and thoracic myelopathy and conus medullaris syndromes have also been reported.

Clinical manifestations of toxoplasmosis in immunocompromised patients also include pneumonitis, chorioretinitis, and multiorgan involvement that presents with acute respiratory failure and hemodynamic abnormalities similar to septic shock.

  • Laboratory findings.Laboratory approaches for the diagnosis of toxoplasmosis include serology, histology with various stains (hematoxylin and eosin, immunoperoxidase, Wright-Giemsa, and periodic acid-Schiff), isolation of the parasite by mouse or tissue culture inoculation, polymerase chain reaction (PCR), and radiological studies (Table 81-1). Histologic examination may reveal the characteristic morphology of the parasite in tissues; the presence of tachyzoites or multiple cysts is diagnostic of active infection. The presence of a solitary cyst may reflect chronic infection unless it is associated with inflammation. Almost any tissue can be inoculated into the peritoneal cavity of mice for isolation studies. Several body fluids can be examined by PCR for the detection of T gondii DNA, including cerebrospinal fluid (CSF), bronchoalveolar lavage fluid, vitreal fluid, aqueous humor, amniotic fluid, urine, and peripheral blood. PCR examination of brain tissue is discouraged because a positive result does not distinguish active from chronic infection.

For any individual in whom toxoplasmosis is considered in the differential diagnosis, the most important initial step is to determine whether the patient has been exposed to the parasite. In virtually all situations, a negative serum immunoglobulin G (IgG) test essentially rules out earlier or recent exposure to the parasite. Rarely, cases of documented toxoplasmic chorioretinitis and TE have been reported in seronegative patients. If IgG antibodies are present and clinical suspicion is high, it is important to establish whether the patient's condition is caused by a recently acquired infection or by reactivation of chronic infection. A true negative IgM antibody test essentially rules out acquisition of the infection within the previous 6 months; however, it does not rule out reactivation of chronic infection. A positive T gondii-specific IgM antibody test can be interpreted in three ways: (1) as a true positive result consistent with recently acquired infection, (2) as a true positive result in the setting of a chronic infection (IgM antibodies have been shown to persist for as long as 5 years after the acute infection), or (3) as a false positive result. To establish which of these is most likely in a given case, confirmatory testing in a reference laboratory should be performed whenever feasible. Confirmatory tests include the Sabin-Feldman dye test, IgM enzyme-linked immunosorbent assay (ELISA), IgA ELISA, IgE ELISA, and differential agglutination test. These tests are available at the Toxoplasma Serology Laboratory at the Palo Alto Medical Foundation (650-853-4828). If the patient has received a blood transfusion, serologic tests may measure antibody acquired exogenously rather than endogenously. The use of serological tests to evaluate the response to therapy should be discouraged.

Table 81-1. Laboratory tests for the diagnosis of toxoplasmosis.

·  Serology (IgG) is useful to establish whether the patient has been exposed to T gondii.1 It can also indicate whether the infection is acute or chronic.2,3

·  Histology (hematoxylin and eosin, immunoperoxidase, Wright-Giemsa and periodic acid-Schiff stains). The presence of tachyzoites is diagnostic of acute infection. Solitary cysts do not necessarily indicate acute or reactivated disease.

·  Isolation of the parasite from any tissue by mouse or tissue culture inoculation is diagonostic.2

·  PCR-based detection of DNA in amniotic fluid, CSF, ocular fluids, bronchoalveolar lavage, peripheral blood, and urine is diagnostic.2

·  Radiographic studies are helpful when suspecting CNS toxoplasmosis in the fetus or newborn (ultrasound or CT) and immunocompromised patients (CT or MRI).

·  In most cases, ocular toxoplasmosis is a clinical diagnosis.

1Confirmatory serological tests include the Sabin-Feldman dye test for IgG, IgM ELISA, IgA ELISA, differential agglutination test, and IgE ELISA.
2Consultation with a reference laboratory is strongly recommended.
3Serological diagnosis may not be useful in immunocompromised individuals.

Despite the crucial role played by members of the feline family in the life cycle of T gondii, a history of cat exposure is not particularly helpful in assessing the likelihood of toxoplasmosis in a given patient. Transmission of T gondii almost always occurs without the awareness of the patient and may be unrelated to direct exposure to cat feces (eg, transmission of oocysts by contaminated vegetables or water). On the other hand, cats that remain indoors at all times and that are fed only cooked food do not pose a risk to humans. Serologic examination of cats should be discouraged; seropositivity does not predict shedding of oocysts.

  • Infection in immunocompetent adults and children.The diagnosis of toxoplasmosis in the vast majority of immunocompetent adults and children relies on serological tests. Recently acquired toxoplasmic lymphadenopathy is easily diagnosed serologically, but, unfortunately, it is not often suspected until after lymph node biopsy. Acute infection is supported by the documented appearance of IgG or IgM antibodies or by a greater than fourfold rise in antibody titer. Histology of appropriate specimens (lymph node or myocardium) may be helpful.

In most cases, toxoplasmic chorioretinitis is diagnosed by and treatment initiated on the basis of ophthalmologic examination and serology test results. PCR analysis of vitreous fluid or the measurement of intraocular production of T gondii-specific IgG antibodies may be useful in patients with presumed toxoplasmic chorioretinitis in whom response to appropriate anti-Toxoplasma therapy is considered inadequate or suboptimal and in patients with atypical eye findings.

  • Infection in pregnant women.The first step in addressing the possibility of toxoplasmosis in pregnancy is to establish whether acute infection has occurred. In the vast majority of cases, the diagnosis of acute infection during pregnancy is only possible with serological testing (Table 81-2). A serological diagnosis should be confirmed by a reference laboratory because the reliability of commercial IgM test kits varies considerably and because the presence of IgM antibody does not necessarily establish the diagnosis of the acute infection (see above).
  • Congenital toxoplasmosis.Prenatal assessment of fetal infection should be performed when a diagnosis of acute infection is established or highly suspected in a pregnant woman. Amplification of T gondii DNA by PCR and/or isolation of T gondii from amniotic fluid establishes the diagnosis of fetal infection and has entirely replaced the testing of blood samples obtained by periumbilical fetal blood sampling. Examination of amniotic fluid should be performed at 18 weeks. The reliability of the PCR test before 18 weeks of gestational age is unknown. The sensitivity of amniotic fluid PCR is ~70%. The sensitivity of inoculation of amniotic fluid into mice for isolation of T gondii is ~ 60%. The specificity of the PCR test is close to 100%. Ultrasonography is a useful test to establish the severity of the infection; however, it should not be used to confirm or rule out congenital toxoplasmosis. Abnormalities frequently reported with this method in cases of in utero infection include ventricular dilatation, intracranial calcifications, increased placental thickness, hepatic enlargement, and ascites.

Table 81-2. Interpretation of Toxoplasma serology in pregnant women.1

IgG result

IgM result

Interpretation and Recommendation



No serologic evidence of infection with T gondii


Equivocal or positive

Possible acute infection or false positive IgM. Send sample to reference laboratory



Indeterminate; obtain a new specimen for testing or retest for IgG in a different assay



Indeterminate; obtain a new specimen for both IgG and IgM testing



Possible acute infection. Send sample to reference laboratory



Infected with T gondii for > 6 months


Equivocal or positive

Possible acute infection. Send sample to reference laboratory

1Modified from US Food and Drug Administration Public Health Advisory: Limitations of Toxoplasma IgM Commercial Test Kits.

The diagnosis of congenital toxoplasmosis in the newborn can be made by detecting specific IgA and IgM antibodies. Serum samples from the newborn should be obtained from peripheral blood and not from the umbilical cord, because it is essential that maternal contamination of blood obtained at birth be excluded. The presence of IgG antibodies in the newborn may reflect passive transplacental transfer of maternal antibodies. Other laboratory tests available for the diagnosis of congenital disease in infants include isolation of the parasite in mice or cell culture (eg, from placental tissue or body fluids) and PCR with body fluids, such as CSF, blood, and urine. Clinical evaluation of infants with presumed T gondii infection should always include ophthalmologic examination, radiologic studies (particularly to detect the presence of cerebral calcifications), and examination of CSF.

  • Infection in immunocompromised patients.It is important to maintain a high index of suspicion for toxoplasmosis in immunodeficient patients because its clinical manifestations are protean and nonspecific and, if left untreated, toxoplasmosis is a source of major morbidity and mortality.

Because reactivation of chronic infection is the most common cause of toxoplasmosis in AIDS- and non–AIDS-immunocompromised patients, the initial routine assessment of these patients, even in the absence of signs of toxoplasmosis, should include a serum T gondii IgG antibody test. Those with a positive result are at risk of reactivation of the infection; those with a negative result should be instructed on how to prevent infection.

The anti-Toxoplasma serologic status of heart transplant recipients should be routinely assessed before transplantation, and an appropriate prophylactic regimen should be instituted for all seronegative hosts if they receive a heart from a seropositive donor.

A definitive diagnosis of toxoplasmosis in the immunodeficient patient relies on histologic demonstration or isolation of the parasite or PCR-based detection of its DNA. In AIDS patients, CSF examination by PCR has been found to have a sensitivity of ~ 80% for the diagnosis of TE. CSF PCR for other organisms has also been found to be helpful in patients with AIDS, including amplification of Epstein-Barr virus, CMV, and JC virus DNA for the diagnosis of primary CNS lymphoma, CMV ventriculitis, and progressive multifocal leukoencephalopathy, respectively.

Computed tomography (CT) or magnetic resonance imaging (MRI) should be obtained when clinical manifestations suggest involvement of the CNS or spinal cord. These studies should be performed even if the neurological examination does not reveal focal deficits. MRI is the radiological test of choice and is more sensitive than CT.

A presumptive diagnosis of CNS toxoplasmosis can be made for patients with multiple ring-enhancing brain lesions (usually established by MRI), positive T gondii-specific IgG antibody titers, and advanced immunodeficiency (eg, CD4 count < 200 or patients who receive intensive immunosuppressive therapy) and justifies anti-Toxoplasma therapy. A clinical and radiologic response to specific therapy within 7–10 days supports the diagnosis.

Brain biopsy should be considered in immunodeficient patients with suspected TE if there is a negative IgG antibody test, a single lesion on MRI, inadequate clinical response to an optimal anti-Toxoplasma treatment regimen, or development of disease in the face of an effective prophylactic regimen against T gondii. In heart transplant patients who present with a clinical syndrome that suggests toxoplasmosis, serologic test results may be misleading. Results consistent with chronic infection may be seen in the presence of acute toxoplasmosis. On the other hand, results that suggest apparent reactivation (rising IgG and IgM titers) may be found in the absence of clinically apparent infection. In these patients endomyocardial biopsy is useful.

Differential Diagnosis

The differential diagnosis of toxoplasmic lymphadenitis includes lymphoma, Epstein-Barr virus-associated infectious mononucleosis, CMV “mononucleosis,” cat scratch disease, sarcoidosis, tuberculosis, tularemia, and metastatic carcinoma. For toxoplasmic encephalitis, the differential diagnosis includes primary CNS lymphoma, JC virus-associated progressive multifocal leukoencephalopathy, CMV ventriculitis, tuberculoma, cryptococoma, and bacterial or nocardial brain abscess. None of the signs described in newborns with congenital disease are pathognomonic for toxoplasmosis, and all of them may be mimicked by congenital infection with other pathogens, including CMV, Treponema pallidum, herpes simplex virus, and rubella virus.


In rare instances, toxoplasmosis causes myocarditis, polymyositis, pneumonitis, hepatitis, or encephalitis in healthy individuals. Early maternal infections sometimes result in death of the fetus in utero and spontaneous abortion.


  • Infection in Immunocompetent Adults and Children.Immunocompetent adults and children with toxoplasmic lymphadenitis do not require treatment unless symptoms are severe or persistent. Infections acquired by laboratory accident or transfusion of blood products are potentially more severe, and these patients should always be treated. The combination of pyrimethamine, sulfadiazine, and folinic acid for 4–6 weeks is the most commonly used and recommended drug regimen (Box 81-2). Treatment should be administered for 2–4 weeks, followed by reassessment of the patient's condition.

The decision to treat active toxoplasmic chorioretinitis should be based on the results of an examination performed by an ophthalmologist. Pyrimethamine and sulfadiazine plus folinic acid are commonly used for this syndrome. Clindamycin has also been used with favorable clinical results. Systemic corticosteroids may be required in addition to the anti-Toxoplasma drugs.

  • Infection in Pregnant Women.Spiramycin is the drug of choice for pregnant women who have acquired primary T gondii infection during gestation (Box 81-3). It does not eliminate but does appear to decrease the incidence of fetal infection. Because there is usually a delay between acquisition of acute maternal infection, infection of the placenta, and subsequent infection of the fetus, identification of acute maternal infection warrants immediate institution of spiramycin [available from the U.S. Food and Drug Administration (301-827-2335)]. Maternal adverse effects associated with spiramycin include nausea, vomiting, anorexia, diarrhea, vertigo, dizziness, flushing of the face, feeling of coolness, and numbness. There is no evidence that spiramycin is teratogenic. Spiramycin should be continued throughout the pregnancy even if the amniotic-fluid PCR result is negative for fetal infection. If the amniotic-fluid PCR result is positive at ≥ 18 weeks, the institution of pyrimethamine, sulfadiazine, and folinic acid is recommended to treat fetal infection in utero.

Pregnant women with toxoplasmic chorioretinitis from reactivation of infection do not experience a higher risk of parasite transmission to the fetus than do pregnant women with prior infection and no ocular disease. However, when toxoplasmic chorioretinitis is thought to be a manifestation of primary infection acquired during gestation, it should be treated, because of the risks to both the mother and the fetus. The advice of an ophthalmologist should be sought.

  • Congenital Toxoplasmosis.The combination of sulfadiazine, pyrimethamine, and folinic acid for ≥ 12 months is a commonly advocated regimen for infants born to mothers with positive results in the amniotic fluid or in whom the disease is highly suspected or proven (Box 81-4).
  • Infection in Immunocompromised Patients.The regimens used to treat toxoplasmosis in immunocompromised patients are basically the same as those used in other clinical settings; however, the doses recommended for immunocompromised patients are usually higher. The standard regimen is the combination of pyrimethamine, sulfadiazine, and folinic (not folic) acid (Box 81-5). Clindamycin can be used instead of sulfadiazine in adult patients intolerant to sulfonamides. The recommended duration of treatment is 4–6 weeks after resolution of all signs and symptoms (often for a total of at least several months). The role of other drugs (eg, atovaquone, clarithromycin, azithromycin, trimethoprim-sulfamethoxazole, and dapsone) in the treatment of toxoplasmosis in immunocompromised patients has not been well established. If these drugs are used, they should be given preferably in combination with pyrimethamine. At the present time, monotherapy does not have a role in the treatment of toxoplasmosis.

In patients with AIDS, after treatment of the acute phase (primary or induction treatment), maintenance therapy (secondary prophylaxis) should be instituted. The maintenance regimen is the same as that used in the acute phase but with each drug at one-half the dose. Current recommendations suggest that maintenance therapy be continued for the life of the patient. It is not known at this time whether the immune reconstitution observed as a result of combination antiretroviral therapy in AIDS patients might allow the successful discontinuation of maintenance treatment. Some non-AIDS-immunocompromised patients may also require maintenance treatment as long as their immunosuppressive regimens continue to exert a significant impact on cell-mediated immunity.

BOX 81-2 Treatment of Toxoplasmosis in Immunocompetent Patients







No therapy1

No therapy1

Chorioretinitis (active), myocarditis, polymyositis, systemic2

·  Pyrimethamine PLUS

·  Loading dose: 2 mg/kg/d (maximum, 50 mg) for 2 days, then maintenance, 1 mg/kg/d (maximum 25 mg)

·  Loading dose: 75–100 mg over 24 h, followed by 25 to 50 mg/d

·  Sulfadiazine3PLUS

·  Loading dose: 75 mg/kg, then maintenance, 50 mg/kg every 12 h (maximum 4 g/d)

·  Loading dose: 2–4 g initially, followed by 1 g four times per day

·  Folinic acid

·  5–20 mg, 3 times weekly

·  5–10 mg/d

·  Corticosteroids (if indicated)

·  1 mg/kg/d in 2 divided doses

·  Dosing varies with clinical setting

1Treatment may be indicated if accompanying symptoms are severe or persistent.
2The role of other regimens, including drugs such as atovaquone, clarithromycin, azithromycin, trimethoprim/sulfamethoxazole, or dapsone, has not been well established.
3Clindamycin (300 mg by mouth every 6 h for a minimum of 3 weeks) is an alternative in patients allergic to sulfonamides.

BOX 81-3 Treatment of Toxoplasmosis in Pregnant Women




Acute infection acquired during gestation

·  Spiramycin (should be continued for the entire pregnancy even if amniotic fluid PCR is negative)

3 g/d

Amniotic fluid PCR–positive result at 18 weeks of gestation or later

·  Pyrimethamine PLUS sulfadiazine PLUS folinic acid starting after 18th wk of gestation

Same doses as for immunocompetent patient

BOX 81-4 Treatment of Toxoplasmosis in Newborns



Pyrimethamine PLUS

Folinic acid

·  Loading dose: 2 mg/kg/d (maximum, 50 mg) or 2 d, then 1 mg/kg/d for 2 or 6 mo. After 2 or 6 mo, 1 mg/kg/d every Monday, Wednesday, and Friday

·  50 mg/kg every 12 h

·  5–20 mg 3 times weekly

Corticosteroids (if indicated)

1 mg/kg/d in 2 divided doses

1Clindamycin is an alternative in patients allergic to sulfonamides.

Prevention & Control

Prevention of the primary infection is of paramount importance in pregnant women and immunodeficient patients who are seronegative (Box 81-6). Tissue cysts in meat are rendered noninfectious by heating the meat to 66°C (meat should be cooked to “well done” with no pink meat visible in the center), by smoking or curing it, or by freezing it to–20°C (which is not achieved in most home freezers). Hands should be washed meticulously after handling raw meat or vegetables; eggs should not be eaten raw, and unpasteurized milk (particularly milk from goats) should be avoided. Flies and cockroaches should be controlled. Areas contaminated with cat feces should be avoided entirely. Disposable gloves should be worn while disposing of cat litter (if this task cannot be avoided altogether), working in the garden, or cleaning a child's sandbox. Oocysts are killed if the cat litter container is soaked in nearly boiling water for 5 min. If the litter container is cleaned every day, oocysts will not have a chance to sporulate.

BOX 81-5 Treatment of Toxoplasmosis in Immunocompromised Patients




Pyrimethamine PLUS

·  Loading dose: 2 mg/kg/d (maximum, 50 mg) for 2 days, then maintenance, 1 mg/kg/d (maximum 25 mg)

·  Loading dose: 200 mg over 24 h, followed by 50–75 mg/d


·  Loading dose: 75 mg/kg, then maintenance, 50 mg/kg every 12 h (maximum 4 g/d)

·  Loading dose: 2–4 g initially, followed by 1–1.5 g four times per day

Folinic acid

·  5–20 mg 3 times weekly

·  5–10 mg/d (≤ 50 mg/d)

1Clindamycin (300 mg by mouth every 6 h for a minimum of 3 weeks) is an alternative in patients allergic to sulfonamides.

BOX 81-6 Prevention of Primary T gondii Infection1

Infectious Form

Preventive Measure

Tissue cyst (meat)

·  Wash hands thoroughly after contact with raw meat

·  Avoid mucous membrane contact when handling raw meat

·  Wash kitchen surfaces and utensils that have come in contact with raw meat

·  Cook meat well done (meat that is cured in brine may be infectious)

·  Avoid ingestion of dried meat

·  Refrain from skinning animals

Oocyst (cat feces)

·  Wash fruits and vegetables before consumption

·  Avoid contact with materials potentially contaminated with cat feces

·  Wear gloves when gardening or handling cat litter

·  Disinfect cat litter with near boiling water for 5 min before handling

1Adapted from Liesenfeld O, Remington JS: Toxoplasmosis. In: Faro S, Soper D (editors) Infectious Diseases in Women: Saunders, Philadelphia, 2001, pp 57–79.

BOX 81-7 Primary Prophylaxis in Immunodeficient Patients



AIDS patients at high risk of developing TE

·  Trimethoprim/sulfamethoxazole (either 160 mg/ 800 mg or 80 mg/400 mg/d) or dapsone (50 mg/d) plus pyrimethamine (50 mg/week)

Heart transplant patients whose donors are seropositive

·  Pyrimethamine (25 mg by mouth once daily for 6 weeks, post–transplant)

There is no vaccine currently available for prevention of toxoplasmosis in humans; primary prophylaxis against toxoplasmosis in patients with AIDS who are at high risk of developing TE has been shown to be effective. Primary prophylaxis is recommended for seropositive patients whose CD4 count has been < 100 cells/mm3 (some experts use a cutoff of < 200 cells/mm3), regardless of the HIV RNA viral load. Trimethoprim-sulfamethoxazole and dapsone plus pyrimethamine have been reported to be effective regimens in preventing the first episode of TE (Box 81-7). Pyrimethamine has been used post-transplantation for primary prophylaxis in seronegative heart transplant recipients whose donors are seropositive (Box 81-7).


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