Toxoplasma gondii

OVERVIEW: What every clinician needs to know

Parasite name and classification

Toxoplasma gondii is an obligate intracellular parasite of worldwide distribution. Members of the Felidae family are the definitive host. Humans and warm-blooded animals are intermediate hosts and primarily harbor the parasite in their brains, eye, heart, and skeletal muscles. The term T. gondii infection (i.e., toxoplasma infection) is best reserved for an asymptomatic individual who is found acutely or chronically infected by serologic testing. The term toxoplasmosis is best applied to the infection that results in symptoms (i.e., disease that occurs in the setting of the acute infection or reactivation of a chronic infection).

What is the best treatment?

Immunocompetent individuals

• Treatment is indicated for immunocompetent patients with severe or ongoing clinical manifestations in the setting of acute infection (see Table 1). Patients may present or develop myocarditis, myositis, hepatitis, pneumonia, or brain or skin lesions. Lymphadenopathy may persist with severe and ongoing constitutional symptoms (e.g., general malaise, fatigue) and fever.

• Treatment is indicated as well for patients with active chorioretinitis due to primary infection or reactivation of a latent infection.

  ---

  Continue Reading

• Duration of treatment has not been established in immunocompetent patients, but the anti-toxoplasma regimen is usually recommended for 3-4 weeks or until symptoms have subsided, whichever is longer.

Table In

During pregnancy and congenital infection

During pregnancy, treatment is recommended for all pregnant women suspected or confirmed of having acquired their primary infection during gestation (Table 2).

Table IIn

• In confirmed gestational cases, treatment is indicated regardless of symptoms in an attempt to prevent transmission of the parasite to the fetus (spiramycin) or, if congenital infection has occurred, to initiate treatment of the fetus (pyrimethamine, sulfadiazine, folinic acid) in utero.

• During pregnancy, treatment regimens are prescribed for the duration of the gestation.

• There has been a worldwide controversy about the efficacy of spiramycin to decrease the incidence of congenital toxoplasmosis. There are no definitive studies proving or disproving its efficacy.

  Two recent studies revealed that spiramycin reduced the rate of vertical transmission, particularly when given within a few weeks of seroconversion and that the use of the spiramycin-pyrimethamine/sulfadiazine/folinic acid strategy resulted in significant decrease in the rates of serious outcomes in the fetus newborn (e.g., severe neurological sequelae and death).

• Pregnant women should be universally screened and, if identified as acutely infected during gestation, treated with the spiramycin-pyrimethamine/sulfadiazine/folinic acid strategy outlined in Table 2.

• Newborns and infants diagnosed with or suspected of having congenital toxoplasmosis should also be treated during the first year of life.

Immunocompromised patients

• Treatment, at higher doses, is also indicated for all immunocompromised patients with toxoplasmosis (see Table 3).

• If untreated, toxoplasmosis in these patients has a very high morbidity and 100% mortality.

• Duration of treatment during the acute phase has not been established, but most clinicians would recommend 4-6 weeks or until most clinical manifestations have resolved, whichever is longer.

• Treatment of the acute phase is usually followed by the maintenance phase (same drugs at half-doses), as long as the immunosuppression is still present. In AIDS patients, maintenance therapy can be discontinued when the CD4 count improves to greater than 200 cells/mm3 and viral load is non-detectable, for longer than 6 months.

Table IIIn

What are the clinical manifestations of infection with this organism?

Primary or acute infection is defined as the first encounter of the individual with the parasite. It requires positive toxoplasma-specific IgG and IgM test results. IgM test results must be confirmed at a reference laboratory (e.g., in the United States, the Palo Alto Medical Foundation Toxoplasma Serology Laboratory, PAMF-TSL), because 60% of positive IgM test results obtained in non-reference laboratories can be observed in patients with chronic infection. During the first 2 weeks of infection, IgG test results can be negative and toxoplasma polymerase chain reaction (PCR) test results in peripheral blood can be positive.

Chronic infection follows the acute infection possibly 6 months after the initial infection when the kinetics of various antibody responses enters into a steady state. All chronically infected individuals remain IgG test positive for life. In rare occasions, IgG commercial tests in these individuals can be negative but positive by the Dye test, considered the “gold standard” for IgG tests. Most of the chronically infected individuals are IgM test negative, but some remain IgM positive for years. Thus, all IgM test positive results must be confirmed at a reference laboratory.

The most important factor for clinicians to consider in laboratory testing for toxoplasma infection or toxoplasmosis should be the clinical setting and not the patient’s epidemiological history. The greatest misconception in today’s clinical practice is to rule out the possibility of toxoplasma infection or toxoplasmosis because the patient does not consume undercooked meat or does not own cats. Up to 50% of infected patients do not recall having been exposed to a risk factor for acute infection or having been ill with a syndrome suggestive of toxoplasmosis.

Immunocompetent individuals

Primary or acute infection in immunocompetent patients can be asymptomatic or result in the following clinical manifestations, alone or in combination:

• Chorioretinitis

• Lymphadenopathy

• Fever

• Headache

• Myalgias

• Arthralgias

• Sore throat

• Stiff neck

• Nausea

• Abdominal pain

• Diarrhea

• Anorexia

• Rash

• Confusion

• Earache

• Eye pain

• General malaise and/or fatigue

Toxoplasmosis should also be considered in cases of unexplained hepatitis, myositis, and/or myocarditis.

In certain areas of the world, including Latin America, certain areas of the United States, and Africa, parasite strains with greater virulence have been reported.

• These strains (Type I, III, or “atypical” have also shown to be of greater virulence in murine models oftoxoplasmosis) have been documented to cause community acquired pneumonia, disseminated disease, and death in immunocompetent patients.

• Toxoplasmic pneumonia has been classically associated with bilateral interstitial pulmonary infiltrates.

• Toxoplasmosis should be entertained in the differential diagnosis of ill returning travelers from these areas of the world who present with unexplained fever, headache, pneumonia, lymphadenopathy, chorioretinitis, myositis, or myocarditis.

Chronic infection in immunocompetent patients is considered essentially asymptomatic with one major exception: chorioretinitis can develop in these individuals as a result of reactivation of their chronic infection. Thus, when evaluating a patient with chorioretinitis, an attempt should be made to establish whether the patient’s eye disease is the result of a concomitant acute infection or reactivation of a previously acquired infection.

• Other clinical manifestations, such as lymphadenopathy, hepatitis, myositis, myocarditis, fever, or non-specific symptoms, have not been documented as reactivation in chronically infected individuals.

• Of note, certain epidemiological studies have linked chronic infection with T. gondii to higher frequency of motor vehicle accidents, behavioral changes, and mental illness, including schizophrenia and bipolar disease. However, the relevance of these associations in clinical practice has not been established.

• For practical purposes, symptoms in immunocompetent patients with the chronic infection should not be attributed to toxoplasmosis, with the exception of chorioretinitis diagnosed by a retinal specialist.

During pregnancy and congenital infection

The primary clinical concern of toxoplasma infection or toxoplasmosis during pregnancy is the fetus. Mother-to-child transmission of the parasite can occur through the placenta in otherwise immunocompetent women who acquire primary infection during gestation or in immunocompromised women who reactivate their chronic infection during gestation (e.g., a pregnant woman with AIDS who develops toxoplasmic encephalitis).

Rarely, mother-to-child transmission has been reported in women who acquired primary infection within 3 months prior to conception.

Vertical transmission does not appear to occur in chronically infected women who are otherwise immunocompetent and develop chorioretinitis as a result of reactivation of the parasite in their retina during pregnancy.

Up to 50% of pregnant women who have acquired their primary infection during gestation do not have a discernible illness suggestive of toxoplasmosis or conventional risk factors for the acute infection.

• If the goal of a clinical practice is to diagnose the primary infection in all their pregnant women, routine serological screening with IgG and IgM must be performed and those found negative should be followed every month to detect seroconversion and institute early prenatal treatment.

• When symptomatic, toxoplasmosis during pregnancy can manifest with similar symptoms as those described above under “primary infection” in immunocompetent individuals.

• Unfortunately, non-specific flu-like symptoms and/or lymphadenopathy have been erroneously attributed to respiratory viruses or streptococcus when, in fact, they were clinical manifestations of the primary infection due to T. gondii.

Congenital toxoplasmosis can result in a wide spectrum of clinical manifestations, ranging from absence of clinical signs at birth to serious neurological sequelae, significant visual impairment, and death of the offspring. However, up to 70% of infected and untreated children who do not have clinical signs at birth will eventually exhibit clinical manifestations of the infection later in life, most often as chorioretinitis.

• In the fetus:

  hydrocephalus

  brain or hepatic calcifications

  splenomegaly

  ascites and pericarditis

• In the newborn:

  non-specific illness (e.g., failure to thrive, diarrhea, hypothermia, petechiae, rash, sepsis)

  strabismus or blindness due to chorioretinitis

  seizures

  abnormal cephalic perimeter (microcephaly or hydrocephalus)

  psychomotor or mental retardation

  intracranial calcifications, due to encephalitis

  hepatosplenomegaly

  pneumonitis

  jaundice

• As the infected offspring phases into childhood and adulthood, clinical manifestations can evolve or appear for the first time, primarily in the form of reactivation of previously existing chorioretinitis or development of new retinal lesions.

Immunocompromised patients

Toxoplasmosis can result in significant morbidity and mortality in immunocompromised patients, including those with AIDS, with transplanted organs, with hematological malignancies, or taking immunosuppressive drugs, such as corticosteroids or certain monoclonal antibodies (e.g., alentuzumab, anti- tumor necrosis factor agents).

Primary infection in immunocompromised patients has been rarely described, with the exception of solid organ transplant patients.

• Acute toxoplasmosis has been reported in seronegative recipients (R-) transplanted with an allograft from an infected donor (D+).

  Organs that have been documented as a source of toxoplasmosis in the solid organ transplant patient include heart, heart-lung, kidney, liver, and liver-pancreas.

  In the D+/R- solid organ transplant patients, toxoplasmosis can present as:

  Fever of unknown origin

  Pneumonia

  Myocarditis

  Hepatitis

  Chorioretinitis

  Brain abscesses

  Although rare, toxoplasmosis has also been documented in D+/R- patients with hematopoietic stem cell (HSC) transplants

In contrast, reactivation of a chronic infection is the primary mechanism for toxoplasmosis in patients with AIDS, HSC transplants, and those taking certain immunosuppressive drugs.

• Toxoplasmosis can develop in 30% of AIDS patients dually infected with T. gondii whose CD4T cell counts decline lower than 200 cells/mm3 and are not taking effective anti-toxoplasma prophylaxis.

  Multiple brain abscesses are commonly described in AIDS patients with toxoplasmic encephalitis.

  Diffuse encephalitis without space-occupying lesions by magnetic resonance imaging (MRI) has been reported with a very high mortality.

  Bilateral interstitial pneumonia has been documented in AIDS patients with toxoplasmic pneumonia.

• Patients chronically infected with T. gondii who undergo an allogeneic HSC transplant and develop graft versus host disease (GVHD) are at higher risk to develop toxoplasmosis in the absence of prophylaxis. In these patients, toxoplasmosis by reactivation can cause:

  Brain abscesses

  Diffuse encephalitis

  Chorioretinitis

  Fever of unknown origin

  Fever alone has frequently been described in patients with allogeneic HSCT patients.

  Pneumonia

  Pneumonia can be the sole manifestation of toxoplasmosis in HSCT patients. Toxoplasmic pneumonitis can present with cough, dyspnea, hypoxia, and diffuse bilateral or localized infiltrates.

  Myocarditis

  Hepatosplenomegaly

  Lymphadenopathy

  Rash

• Reactivation in heart tissue can cause:

  Congestive heart failure

  Arrhythmias

  Pericarditis

Do other diseases mimic its manifestations?

Immunocompetent individuals

• Chorioretinitis with atypical features for toxoplasmosis can mimic viral chorioretinitis caused by herpes simplex (HSV), varicella zoster virus (VZV) or occasionally by cytomegalovirus (CMV); in addition, chorioretinitis caused by syphilis and toxocara.

• Acute toxoplasmosis causing systemic symptoms can mimic upper respiratory viral infections, streptococcal pharyngitis, and infectious mononucleosis-like syndrome.

• Acute toxoplasmosis causing lymphadenopathy can mimic streptococcal or staphylococcal lymphadenitis or infection due to Bartonella spp, mycobacteria, or endemic fungi. Lymphadenopathy due to T. gondii can also initially mimic lymphoma.

• Acute toxoplasmosis causing diarrhea and abdominal pain can mimic viral gastroenteritis or food poisoning.

• Acute toxoplasmosis causing hepatitis can mimic viruses causing hepatitis, including Hepatitis A, Hepatitis B, Hepatitis C, CMV, EBV, HHV-6.

• Acute toxoplasmosis causing pneumonia can mimic atypical pathogens such as Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella pneumophila, or viruses. It can also mimic diffuse alveolar hemorrhage or acute drug reactions.

• Acute toxoplasmosis causing myocarditis can mimic enteroviruses, influenza, HHV-6, parvovirus B19, and Borrelia burgdorferi.

During pregnancy and congenital

• Acute toxoplasmosis during pregnancy, when symptomatic, can mimic upper respiratory viral infections, streptococcal pharyngitis, or infectious mononucleosis-like syndrome.

• In the fetus and newborn, toxoplasmosis can mimic congenital infections caused by CMV, syphilis, rubella, parvovirus B19 or HHV-6, and peripartum infections, such as those caused by HSV or bacterial infections.

Immunocompromised patients

• Toxoplasmic pneumonia can mimic pneumonia due Pneumocystis jiroveci (PCP), atypical pathogens, such as Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella pneumophila, or viruses. It can also mimic diffuse alveolar hemorrhage or acute drug reactions.

• Brain abscesses due to T. gondii can mimic primary central nervous system (CNS) lymphoma, progressive multifocal leukoencephalopathy (PML), and Chagas disease.

• Fever of unknown origin can be the sole presenting feature toxoplasmosis.

• Myocarditis due to toxoplasma can mimic CMV, EBV, opportunistic and endemic fungi.

What laboratory studies should you order and what should you expect to find?

Serologic tests, including T. gondii-specific IgG, IgM, and IgG avidity, polymerase chain reaction, and visualization of the parasite in cytological and histological slides, are frequently used in non-reference laboratories for the diagnosis of T. gondii infection and toxoplasmosis. Positive or negative results in IgG tests and negative results in IgM tests performed in non-reference, commercial, or hospital-based laboratories are reliable. All positive IgM test results obtained in these laboratories must be sent for confirmatory testing to a reference laboratory, because only 40% of these positive results truly reflect an acute infection. Reference laboratories have the capacity to establish whether a positive or equivocal IgM test result is truly indicative of an acute infection.

The diagnosis of reactivation of a chronic infection in immunocompromised patients requires:

• The visualization of tachyzoites in any body fluid or tissue

• A successful amplification of the parasite DNA in any body fluid

• T. gondii-specific immunohistochemistry that reveals the presence of parasite antigens surrounded by an inflammatory response

Immunocompetent individuals

• Toxoplasma-specific IgG and IgM (can be performed at any commercial, non-reference, or hospital-based laboratory): Initial serological screening should be performed to determine whether the patient has ever been infected or is acutely or chronically infected.

  Negative IgG and negative IgM: If the patient is capable to produce IgG and IgM, there is no serologic evidence of T. gondii infection. If deficiency in generalized production of IgG or IgM is suspected, consider testing for total IgG or IgM tests. If the patient is not capable of producing IgG or IgM, consultation with a reference laboratory is advised (e.g., PAMF-TSL = Palo Alto Medical Foundation Toxoplasma Serology Laboratory: http://www.pamf.org/serology/).

  Positive IgG and negative IgM: The patient has been infected with T. gondii for some time, probably for more than 3-6 months. If onset of symptoms or disease is within 3-6 months of serum sampling, it is unlikely that symptoms can be attributed to toxoplasmosis.

  Positive IgM, regardless of the IgG test result: Confirmatory testing of the positive IgM test result must be sent to a reference laboratory (e.g., PAMF-TSL = Palo Alto Medical Foundation Toxoplasma Serology Laboratory: http://www.pamf.org/serology/) for confirmatory testing. A positive IgM test result can be observed in acute or chronic infections.

During pregnancy and congenital infection

The first goal of laboratory testing during pregnancy is to establish whether the woman was infected during gestation.

• Women suspected or confirmed to have acquired their infection during gestation or shortly before conception (e.g., within 3 months of conception) are at risk to transmit the parasite to the offspring.

• Women infected in the distant past and prior to gestation are essentially at no risk for congenital toxoplasmosis, unless they are immunocompromised (i.e., HIV-positive, receiving corticosteroids or immunosuppressive drugs, etc.).

• Recent reports have documented cases of congenital toxoplasmosis in women who were chronically infected with parasite strains of low virulence but were infected during gestation with a strain of greater virulence. At this time, this latter scenario is considered of rare occurrence.

• Toxoplasma-specific IgG and IgM (this initial screening can be performed at any commercial, non-reference, or hospital-based laboratory): Initial serological screening should be performed in each pregnant woman to determine if the patient has ever been infected (thus, at risk to acquire infection during gestation and transmit the parasite to the fetus), acutely infected (at risk to transmit the parasite to the fetus), or chronically infected (i.e., acquired the infection prior to gestation therefore with essentially no risk to transmit the parasite to the fetus, unless immunocompromised).

  Negative IgG and negative IgM: If the pregnant woman is capable to produce IgG and IgM, there is no serologic evidence of T. gondii infection.

  Positive IgG and negative IgM: The pregnant woman has been infected with T. gondii for some time, probably for more than 3 months (if IgG titers are “high” [e.g., dye test IgG >1024]) or 6 months (if IgG titers are “low” [e.g., dye test IgG < or = to 1024]).

  Positive IgM, regardless of the IgG test result: Confirmatory testing of the positive IgM test result must be sent to a reference laboratory (e.g., PAMF-TSL = Palo Alto Medical Foundation Toxoplasma Serology Laboratory: http://www.pamf.org/serology/) for confirmatory testing. A positive IgM test result can be observed in acute or chronic infections.

Immunocompromised patients

• Toxoplasma-specific IgG: Initial screening with a toxoplasma-specific IgG test should be performed in all individuals before they become immunosuppressed or shortly after the status of immunosuppressed host has been ascertained. A positive IgG antibody test establishes that the patient has been infected and is at risk of reactivation during periods of significant immunosuppression. Of note, serological tests obtained during or following significant immunosuppression may be misleading and are often not helpful in establishing whether the patient is suffering from acute or reactivated toxoplasmosis. For instance, a positive titer pre-immunosuppression may rise, fall, or totally disappear post-transplant or during immunosuppression, regardless whether the patient has toxoplasmosis or not. In addition, solid organ transplant recipients face an additional challenge, because their allograft has the potential to transmit the parasite to the transplanted patient (e.g., heart, heart-lung, kidney, kidney-pancreas, liver, liver-pancreas). Thus, in addition to the transplant candidate, once identified, solid organ donors should also be tested for T. gondii–specific IgG to identify D+/R- pairs

• PCR, direct visualization of tachyzoites in body fluids or tissues by microscopy examination, histological examination, and/or isolation can be attempted for the diagnosis of toxoplasmosis in an immunocompromised patient who presents with symptoms and signs suggestive of the disease.

• Brain and spinal cord imaging studies (e.g., MRI) should be obtained in immunocompromised patients who present with CNS symptoms and/or signs.

Immunocompetent individuals

Serological testing is the primary laboratory modality used. Non-reference laboratories can successfully determine whether an individual has ever been infected (i.e., negative IgG and negative IgM test results) or has been chronically infected (i.e., positive IgG and negative IgM test results).

• Negative IgG and negative IgM: Assuming the patient is capable of producing IgG antibodies, there is no serologic evidence of T. gondii infection.

• Positive IgG and negative IgM at any laboratory, including non-reference, commercial, or hospital-based, confirms the patient has been infected with T. gondii for some time, probably for more than 3-6 months.

• Positive IgM, regardless of the IgG test result: Confirmatory testing of the positive IgM test result must be sent to a reference laboratory (e.g., PAMF-TSL = Palo Alto Medical Foundation Toxoplasma Serology Laboratory: http://www.pamf.org/serology/) for confirmatory testing. A positive IgM test result can be observed in acute or chronic infections.

• Confirmatory testing for positive IgM test results include IgG avidity testing, AC/HS (or differential agglutination), and IgA and IgE serological tests. A high IgG avidity test result indicates the patient has been infected at least 3-5 months (window varies with the method used) from the date of serum sampling. A non-acute pattern in the AC/HS will indicate that the patient has been infected at least 12 months. A positive IgA and IgE test result will suggest the patient has been infected for less than 3 months. Low or equivocal IgG avidity test results or acute or equivocal patterns in the AC/HS cannot be interpreted as necessarily indicative of an acute infection.

• PAMF-TSL will perform various combinations of confirmatory tests to arrive at one of three final interpretations: a recently acquired infection (or primary infection), therefore, clinical manifestations could be attributed to toxoplasmosis; an infection acquired in the distant past (chronic or latent infection), thus, assuming that the patient is otherwise immunocompetent, clinical manifestations are unlikely to be attributable to toxoplasmosis; or equivocal results, a follow up sample is required to be tested in parallel with existing sample and ascertain a recently acquired or chronic infection.

• The diagnosis of ocular toxoplasmosis represents a unique challenge.

• Ophthalmologists specialized in retinal infections can make the presumptive diagnosis of toxoplasmic chorioretinitis by funduscopic examination.

  The morphology of the retinal lesions is thought to be characteristic of toxoplasmosis.

  An active whitish infiltrate originates from a darkly pigmented border of an older scar.

  The presence of vitritis can give the “headlight in the fog” appearance.

• In the case of typical retinal lesions, IgG and IgM serologies should be obtained to confirm the patient has been infected with T. gondii and to establish whether the eye disease is:

  the result of a concomitant acute infection (positive IgG and positive IgM confirmed at a reference laboratory)

  reactivation of an infection acquired in the distant past (positive IgG and negative IgM): In this setting, response to anti-toxoplasma therapy is considered to be an additional diagnostic criterion in favor of the diagnosis of ocular disease due to toxoplasmosis.

• Toxoplasmic chorioretinitis tends to be less typical in certain individuals, including older patients and immunocompromised patients.

  If retinal lesions are atypical or there is inadequate response to anti-toxoplasma treatment, sampling of ocular fluids (vitreous fluid or aqueous humor) for PCR testing should be considered if clinically indicated and the procedure is considered safe and feasible.

During pregnancy and congenital infection

• Negative IgG and negative IgM: Assuming the patient is capable of producing IgG antibodies, there is no serologic evidence of T. gondii infection. Consider testing the patient for toxoplasma IgG and IgM every 4-8 weeks for the duration of her gestation. Advise the patient to avoid exposure to T. gondii during pregnancy (see Table 4). If deficiency in generalized production of IgG or IgM is suspected, consider testing for total IgG or IgM tests. If the patient is not capable of producing IgG or IgM, consultation with a reference laboratory is advised. (e.g., PAMF-TSL = Palo Alto Medical Foundation Toxoplasma Serology Laboratory: http://www.pamf.org/serology/).

• Positive IgG and negative IgM: If serum sample was obtained within 3 months (along with “high” IgG titers) or within 6 months (along with “low” IgG titers), serologic test results will be consistent with an infection acquired prior to this pregnancy. The incidence of congenital toxoplasmosis in offspring of women infected prior to gestation has been shown to be extremely rare (approaching zero), unless the woman is immunocompromised (i.e., HIV-positive, receiving corticosteroids or immunosuppressive drugs, etc.).

• Positive or equivocal IgM, regardless of the IgG test result: Confirmatory testing of the positive IgM test result must be sent to a reference laboratory (e.g., PAMF-TSL = Palo Alto Medical Foundation Toxoplasma Serology Laboratory: http://www.pamf.org/serology/) for confirmatory testing. A positive IgM test result can be observed in acute or chronic infections.

• Confirmatory testing for positive IgM test results at PAMF-TSL include IgG avidity testing, AC/HS (or differential agglutination), and IgA and IgE serological tests. A high IgG avidity test result indicates the patient has been infected for at least 3-5 months (window varies with the method used) from the date of serum sampling. A non-acute pattern in the AC/HS indicates the patient has been infected for at least 12 months. A positive IgA and IgE test result suggests the patient has been infected for less than 3 months. Low or equivocal IgG avidity test results or acute or equivocal patterns in the AC/HS cannot be interpreted as necessarily indicative of an acute infection

• PAMF-TSL will perform various combinations of confirmatory tests to arrive at one of three final interpretations: a recently acquired infection (or primary infection), therefore, the possibility of the patient having acquired the infection during pregnancy cannot be excluded; an infection acquired in the distant past (chronic or latent infection) and prior to the pregnancy; and equivocal results, a follow-up sample is required to be tested in parallel with existing sample and ascertain the diagnosis of a recently acquired or chronic infection.

• Once it has been established that an acute infection was likely acquired during gestation or shortly before conception, fetal infection should be ruled out by testing the amniotic fluid by PCR at 18 weeks of gestation.

  The positive predictive value of this test is approximately 100%.

  The negative predictive value approaches 100%, if the maternal infection was acquired early in the first trimester but decreases considerably if acquired late in gestation.

Table IVn

Immunocompromised patients

• The diagnosis of toxoplasmosis in immunocompromised patients can be primarily made by a positive PCR test in any body fluid (e.g., peripheral blood, bronchoalveolar lavage, cerebrospinal fluid, vitreous fluid) or visualization of the tachyzoite form in any body fluid or tissue.

• A positive PCR test result has a 100% positive predictive value when obtained in body fluids (assuming there are no issues of contamination in the laboratory performing the test). In contrast, positive PCR test results in tissue should be interpreted with caution, as they may also reflect the mere presence of tissue cysts in a chronically infected individual who has not reactivated T. gondii and whose symptoms should be attributed to a diagnosis other than toxoplasmosis.

• Direct visualization of tachyzoites in body fluids or tissues by microscopic examination can also be diagnostic of toxoplasmosis. Tachyzoites can be stained with Wright-Giemsa stain in body fluids, and Hematoxylin and Eosin (H&E) or T. gondii-specific immunoperoxidase in tissue biopsy specimens.

• Brain and spinal cord imaging studies (e.g., MRI): Neuroimaging studies play a unique role in the diagnosis of toxoplasmic encephalitis (TE) in patients with AIDS. In HIV infected individuals, the diagnosis of TE can be established as probable in patients who present with multiple ring-enhancing brain occupying lesions (often involving the basal ganglia), have been documented to be infected with T. gondii (e.g., positive toxoplasma-IgG), have developed AIDS (e.g., CD4 count below 200 cells/mm³), and are not taking anti-toxoplasma prophylaxis.

  In this setting, a response to treatment within 7-10 days of appropriate anti-toxoplasma therapy is considered as additional diagnostic criteria of TE.

  HIV-infected patients who do not present with this constellation of neuroimaging studies (e.g., single brain occupying lesion) and laboratory test results (e.g., negative toxoplasma IgG, CD4 count greater than 200 cell/mm³) and who are taking appropriate anti-toxoplasma prophylaxis are less likely to have TE and more likely to have an alternative diagnosis for their brain space-occupying lesions (e.g., EBV-related primary central nervous system lymphoma, JC virus-related progressive multifocal leukoencephalopathy, CMV ventriculitis). In the latter setting, CSF PCR (e.g. for T. gondii, EBV, or CMV) or brain biopsy should be considered for the definitive diagnosis of the brain lesion(s).

  In contrast to the diagnostic algorithm described for AIDS patients, the diagnosis of TE cannot be supported by neuroimaging studies in non-AIDS immunosuppressed patients, because, in these patients, brain biopsy should be considered as the first diagnostic step in this patient population as well.

• Attempts to isolate the parasite from body fluids can be attempted by research laboratories for genotyping and research purposes.

What imaging studies will be helpful in making or excluding the diagnosis of Toxoplasma gondii ?

• For suspicion of brain or spinal cord involvement, MRI with gadolinium is the imaging study of choice. Several studies have demonstrated the greater sensitivity of MRI over CT for the diagnosis of CNS toxoplasmosis.

• For suspicion of pulmonary involvement, CT of the chest without contrast is the radiologic study of choice. Several studies have demonstrated the greater sensitivity of chest CT over CXR for the diagnosis of pulmonary toxoplasmosis

What complications can be associated with this parasitic infection, and are there additional treatments that can help to alleviate these complications?

Immunocompetent individuals

• Patients with ocular disease can be left with serious visual sequelae or blind.

• Immunocompetent patients with acute toxoplasmosis can develop significant morbidity (e.g., acute community-acquired pneumonia or myocarditis that requires admission to the Intensive Care Unit). Deaths due to acute toxoplasmosis have been reported in these patients from several tropical areas

During pregnancy and congenital infection

• The primary concern of toxoplasmosis during pregnancy is whether the parasite has been transmitted to the fetus. The newborn can be born apparently normal but develop new lesions of chorioretinitis later in life. Newborns and children can also develop serious disease, including hydrocephalus, intracranial calcifications, chorioretinitis, hearing deficits, neurological sequelae, or hematological abnormalities.

Immunocompromised patients

• If untreated, toxoplasmosis in immunocompromised patients is essentially 100% lethal.

What is the life cycle of the parasite, and how does the life cycle explain infection in humans?

T. gondii primarily exists in three infectious forms:

• Tachyzoite (formerly known as trophozoite) is the rapidly replicating form responsible for the clinical manifestations and dissemination of the parasite in patients with toxoplasmosis. A well-orchestrated and healthy immune response is capable of transforming tachyzoites into bradyzoites.

• Bradyzoite is the metabolically hibernating form contained in tissue cysts and is responsible for the chronic state of the infection. Bradyzoites can be transformed back into tachyzoites when significant T-cell mediated immunodeficiency develops.

• Oocyst is the form excreted by infected cats (domestic and wild) and responsible for its wide dissemination in nature. Although the presence of domestic or wild cats are required for the existence and dissemination of the parasite in nature, in most epidemiological studies, cat ownership does not correlate with the presence of toxoplasma infection in humans.

Although patients may inadvertently become infected with the parasite without having a recognized risk factor for acute infection, educational efforts should be implemented to decrease the likelihood of infection through known routes of transmission (Table 4).

• The majority of epidemiologic studies worldwide have recognized contaminated and undercooked meat as one of the main risk factors for the transmission of the parasite. This appears to be the case in Europe, North America, and Latin America.

  Tissue cysts in meat are rendered nonviable by γ-irradiation (0.4 kGy), heating throughout to 67°C, or freezing to −20° C for 48 hours and then thawing.

  Cured, dried, or smoked meat should not be considered toxoplasma free and has been associated with the acute infection.

• Soil exposure and soil-related activities have been reported to play a more prominent role in transmission in certain geographic areas in the United States and Latin America.

How does this organism cause disease?

After oral infection with tissue cysts (e.g., present in contaminated meat) or oocysts (e.g., in contaminated soil or water or food), the wall of both infectious forms is disrupted by enzymes present in digestive juices of the stomach. Bradyzoites and sporozoites are released from cysts and oocysts, respectively, and converted to the tachyzoite form. Tachyzoites have the capacity to infect contiguous cells and distant tissues by hematogenous dissemination or lymphatic spread. Tachyzoites appear to actively and rapidly migrate across epithelial cells and travel to distant sites (acute infection). Their histologic hallmark is necrosis surrounded by inflammation.

In immunocompetent individuals, the immune system controls the proliferation of the tachyzoite and induces its reversion back to the bradyzoite form, facilitating the final formation of tissue cysts (chronic infection). Tissue cysts persist for the life of the host, and T. gondii can be isolated from tissues of individuals who have died by causes other than toxoplasmosis. It appears that the activation of well-orchestrated immune responses is required for the successful resistance against T. gondii. Innate, humoral, and cellular immune responses likely involved in preventing the uncontrolled proliferation of tachyzoites include activation of the monocyte-macrophage system, dendritic cells, natural killer cells, and αβ and γδ T-cells; T. gondii–specific and cytotoxic CD4+ and CD8+ T-cells; and interferon-γ, interleukin-12, tumor necrosis factor-α, interleukin-10, and other cytokines, transforming growth factor-β, costimulatory molecules (e.g., CD28, CD40 ligand), and, to a lesser degree, immunoglobulins.

In immunocompromised patients previously infected with T. gondii, decreased T-cell-mediated immune responses can facilitate the reactivation of their infection (i.e., conversion of bradyzoites in their tissue cysts into rapidly proliferating tachyzoites).

There is no evidence for person to person transmission of T. gondii.

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

Boyer, K, Hill, D, Mui, E. “Unrecognized ingestion of Toxoplasma gondii oocysts leads to congenital toxoplasmosis and causes epidemics in North America”. Clin Infect Dis. vol. 53. 2011 Dec. pp. 1081-9.

Boyer, KM, Holfels, E, Roizen, N. “Risk factors for Toxoplasma gondii infection in mothers of infants with congenital toxoplasmosis: Implications for prenatal management and screening”. Am J Obstetrics Gynecol. vol. 192. 2005 Feb. pp. 564-71.

Cortina-Borja, M, Tan, HK, Wallon, M. “Prenatal treatment for serious neurological sequelae of congenital toxoplasmosis: an observational prospective cohort study”. PLoS Med. vol. 7. 2010. pp. pii: e1000351

Dunn, D, Wallon, M, Peyron, F, Petersen, E, Peckham, C, Gilbert, R. “Mother-to-child transmission of toxoplasmosis: risk estimates for clinical counseling”. Lancet. vol. 353. 1999. pp. 1829-33.

Jones, JL, Dargelas, V, Roberts, J, Press, C, Remington, JS, Montoya, JG. “Risk factors for Toxoplasma gondii infection in the United States”. Clin Infect Dis. vol. 49. 2009 Sep 15. pp. 878-84.

Luft, BJ, Hafner, R, Korzun, AH. “Toxoplasmic encephalitis in patients with the acquired immunodeficiency syndrome”. N Engl J Med. vol. 329. 1993. pp. 995-1000.

Montoya, JG, Remington, JS. “Management of Toxoplasma gondii infection during pregnancy”. Clin Infect Dis. vol. 47. 2008 Aug 15. pp. 554-66.

Olariu, TR, Remington, JS, McLeod, R, Alam, A, Montoya, JG. “Severe congenital toxoplasmosis in the United States: clinical and serologic findings in untreated infants”. Ped Infect Dis J. vol. 30. 2011 Dec. pp. 1056-61.

Phan, L, Kasza, K, Jalbrzikowski, J. “Longitudinal study of new eye lesions in children with toxoplasmosis who were not treated during the first year of life”. Am J Ophthalmol. vol. 146. 2008 Sep. pp. 375-84.

“Limitations of Toxoplasma IgM Commercial Test Kits”. 1997.

Remington, JS, McLeod, R, Thuilliez, P, Desmonts, G, Remington, JS, Klein, JO, Wilson, CB, Nizet, V, Maldonado, Y. “Toxoplasmosis”. Infectious diseases of the fetus and newborn infant. 2011.

Thiebaut, R, Leproust, S, Chene, G, Gilbert, R. “Effectiveness of prenatal treatment for congenital toxoplasmosis: a meta-analysis of individual patients' data”. Lancet. vol. 369. 2007 Jan 13. pp. 115-22.

Wallon, M, Kodjikian, L, Binquet, C. “Long-term ocular prognosis in 327 children with congenital toxoplasmosis”. Pediatrics. vol. 113. 2004 Jun. pp. 1567-72.

Copyright © 2017, 2013 Decision Support in Medicine, LLC. All rights reserved.

No sponsor or advertiser has participated in, approved or paid for the content provided by Decision Support in Medicine LLC. The Licensed Content is the property of and copyrighted by DSM.