OVERVIEW: What every practitioner needs to know
Are you sure your patient has Toxoplasma gondii infection? What are the typical findings for this disease?
Toxoplasma gondii is lifelong. The most common symptoms and clinical findings are dependent on: 1) timing of infection, and 2) immunocompetency of the infected individual.
Fetus and newborn (congenital infection):
—Most infections are subclinical but develop late sequelae
—Chorioretinitis with vision impairment
—Neurological and neurodevelopmental deficits
—Hepatosplenomegaly and jaundice
—Usually subclinical without long-term sequelae
—Chorioretinitis with blurred vision
— Diffuse systemic disease with meningitis, encephalitis, pneumonitis, myocarditis
Clinical manifestations of Toxoplasma gondii infection
Toxoplasma gondii is an obligate intracellular protozoan parasite named for its shape (toxoplasma means arc-like form) and the rodent from which it was first isolated (Ctenodactylus gundi). T. gondiiis found in many animal species throughout the world. It was first described in association with infant disease by Janku in 1923.
Most infections in normal hosts are asymptomatic, but serious localized and and systemic disease may occur in the fetus and newborn, and in immunodeficient children.
Acquired infection in immunocompetent hosts
Most cases of Toxoplasma infection in both children and adults, including pregnant women, are subclinical in the setting of normal immune function. Disease is usually self-limiting, with nonsuppurative lymphadenopathy being the most frequently recognized manifestation. Single site adenopathy is more common in adults compared with multiple sites in children. The most frequently involved nodes are cervical, followed by axillary and inquinal. Adenopathy may persist for 1 to 2 months.
Other clinical presentations include fever, malaise, and myalgia. In some cases, a maculopapular rash has been described. Rarely, muscle, visceral organ, brain or meningeal inflammation has been reported in apparently normal children. Ocular disease may also occur from acute acquired Toxoplasma infection in normal hosts, although this has more commonly been described with congenital and reactivated disease. More recent studies have suggested that chorioretinitis associated with acute acquired Toxoplasma infection may be more common than previously recognized.
Toxoplasmosis in immunocompromised hosts
Toxoplasmosis in immunocompromised persons may present with disseminated infection with fever and multiple organ involvement, including brain, heart, and lung. Clinical findings may include retinal disease, encephalitis, pneumonitis, myocarditis, or multiorgan disease. Disease may occur from a newly acquired infection, or reactivation of a previously acquired infection in individuals who develop an immunodeficiency disorder or are receiving immunosuppressive therapy. Primary infection can occur also in transplant recipients receiving an infected organ or bone marrow, or through blood transfusion.
Chorioretinitis. Multiple active chorioretinal lesions may occur in immunocompromised patients, with both unilateral and bilateral involvement. Necrosis associated with large numbers of tachyzoites has been identified in histopathology specimens. Old lesions, which may be seen with reactivated disease in immunocompetent patients, may not be present. Lesions are often perivascular, suggesting hematologic spread.
Encephalitis. Toxoplasma encephalitis may occur in adult AIDS patients, particularly in those with very low CD4 counts. Many of these cases appear to be due to reactivation of chronic Toxoplasma infection. Symptoms include headache, confusion/altered consciousness, seizures, motor impairment, and focal weakness.
— The incidence of Toxoplasma encephalitis is much less common in children with AIDS, possibly due to a low rate of chronic Toxoplasma infection.
— Pediatric Toxoplasma encephalitis may be seen in the absence of documented immunodeficiency.
— In one study, 9 of 32 children with Toxoplasma encephalitis did not have a recognized underlying immunodeficiency.
Congenital Toxoplasma infection has three general categories of clinical presentation:
— Subclinical infection
—Clinically apparent disease observed in the fetus, neonate, or young infant
— Late sequelae in later infancy, childhood, or adolescence
Subclinical infection: Congenital Toxoplasma infection is subclinical in up to 90 percent of infected fetuses and newborns, and no manifestations of disease are found on routine fetal ultrasound surveys or physical examination at birth. These subclinical infections largely go undiagnosed in the absence of a screening program, unless further evaluation is undertaken because of suspected or proven maternal infection during pregnancy. Abnormalities are identified, however, in a significant number of these subclinical infections when the newborns are evaluated by cerebrospinal fluid (CSF) sampling, detailed pediatric ophthalmologic examination, and central nervous system (CNS) imaging.
Among 48 infants with normal routine newborn examinations who were diagnosed with congenital Toxoplasma infection solely through a newborn screening program (New England Newborn Screening Program), 40 percent had CNS or retinal abnormalities. In these infants: 1) the ophthalmologic lesions often consisted of unilateral macular retinal scars, 2) small, focal cerebral calcifications were found by intracranial imaging (usually head CT scan), and 3) CSF profiles showed mild to moderate protein elevation (rarely >1 g/dL), and sometimes a mononuclear CSF pleocytosis.
Clinically apparent disease: Signs and symptoms of congenital toxoplasmosis are present in only 10 to 30 percent of infants at birth. The clinical findings may be multiple and nonspecific, but ocular and CNS disease are characteristic, and even in infants initially presenting with generalized systemic manifestations, the ocular and CNS abnormalities are the end result of infection. Table I lists the clinical features that have been noted in infants with clinically apparent toxoplasmosis.
|Clinical features in infants with clinically apparent toxoplasmosis: Summary from published case series|
|Clinical findings||Approximate percent ofcases (%)|
|Intracranial calcification||35 to 85|
|Abnormal cerebrospinal fluid||65|
|Jaundice||40 to 60|
|Anemia||50 to 60|
Late manifestations: Newborns with mild or subclinical congenital Toxoplasma infection at birth remain at significant risk for long-term sequelae, particularly if they do not receive extended anti-Toxoplasma therapy. Similarly, infants with an early presentation of clinically apparent disease may have disease progression in the absence of extended anti-Toxoplasma therapy.
Chorioretinitis. The most common and consistently documented late manifestation is chorioretinitis. New-onset or reactivated retinal disease occurs in 90 percent or more of children with untreated congenital Toxoplasma infection, regardless of the initial clinical presentation. The risk of new ocular disease extends into adulthood, with the peak incidence thought to occur during the second to third decades of life. Episodic recurrences of chorioretinitis may still occur despite early, extended anti-Toxoplasma therapy, but the incidence appears to be significantly decreased.
Symptoms include blurred vision, photophobia, epiphora, and vision loss. The typical lesion is a unilateral, focal necrotizing macular retinitis with a yellow-white, raised, and well demarcated appearance. Following this acute inflammatory phase, the lesion heals as a pale scar with dark pigmentation.
Uveitis and vitritis may occur, and complications may include permanent vision loss, retinal detachment, and neovascularization of the retina and optic nerve. Strabismus may be present, and newborns presenting with clinically apparent disease may have microphthalmia, cataract, nystagmus, glaucoma, and changes in the iris.
CNS-related late manifestations. Other late manifestations of congenital Toxoplasma infection are primarily associated with CNS disease. In the absence of an early extended anti-Toxoplasma treatment regimen, infants are at risk for developing:
— Motor and cerebellar dysfunction
— Intellectual disability (mental retardation)
— Sensorineural hearing loss
Endocrine abnormalities associated with hypothalamic-pituitary dysfunction have also been described, including growth retardation and precocious puberty.
Studies have varied in the reported incidence of late neurological sequelae in infants with subclinical infection at birth. One study reported on 13 children diagnosed with congenital Toxoplasma infection by serology, but who were treated for only 1 month or less with anti-Toxoplasma drugs. None of the 13 had clinical findings of Toxoplasma disease by examination, including ophthalmologic evaluation. In those infants who were available for follow-up out to 10 years, 3 of 10 had sensorineural hearing loss, and 5 of 13 had neurologic abnormalities, one with severe neurodevelopmental delay, seizures, and microcephaly, and 2 with persistent cerebellar dysfunction. The mean IQ for all 13 children was 88.6, and for 6 children available for retesting 5.5 years apart, the mean IQ fell from 96.6 to 74. Two children had severe reduction in IQ to 36 and 62. Eleven of 13 had new-onset chorioretinitis consistent with other studies.
Eleven infants diagnosed with congenital Toxoplasma infection and followed for 20 years in Amsterdam again demonstrated the high incidence of chorioretinitis, which developed in 9 of 11 with severe visual impairment in 4 and unilateral blindness in 1. All 11 individuals, however, were said to have had normal school performance.
The cumulative experience with managing congenital Toxoplasma infections indicate that all infected infants should be considered at risk for disease progression and late neurologic sequelae, whatever the initial clinical presentation at birth.
What other disease/condition shares some of these symptoms?
Differential diagnosis in immunocompetent children and adults
Most acute infections are asymptomatic or may present with generalized viral-like symptoms. Two clinical presentations in otherwise normal children and adults are persistent adenopathy and ocular disease. Each of these has a broad differential diagnosis. A careful history, including onset and progression of symptoms, potential infectious exposures, and the occurrence of other related symptoms such as fevers and weight loss, may help direct the laboratory evaluation.
— Bacterial lymphadenitis
— Viral infections
— Infectious mononucleosis (Epstein-Barr virus)
— Cytomegalovirus (CMV)
—Human immunodeficiency virus (HIV)
— Cat-scratch disease
— Atypical Mycobacteria
— Reactivation of congenital retinal disease
— Fungal retinitis
— Mycobacterium tuberculosis
— Toxocara infection
— Baylisascaris procyonis (raccoon roundworm) infection (may present as a diffuse, subacute neuroretinitis)
Differential diagnosis in immunocompromised children
Clinical recognition of disseminated toxoplasmosis may be difficult because of non-specific clinical findings. Toxoplasmosis should always be considered in acutely ill immunocompromised children, especially with new-onset vision disturbances, neurological symptoms, myocarditis, or pneumonitis. Initial sympotms may be subacute and generalized, but disease can become rapidly fulminant, with severe multiorgan disease. The differential diagnosis is broad, depending on the clinical presentation and organ involved.
Toxoplasma retinal disease
— Herpes simplex virus
— Fungal infection
— Any other cause of retinitis in children
— CNS lymphoma
— Progressive multifocal leukoencephalopathy
— Bacterial abscess
— Mycobacterium tuberculosis
— Focal viral encephalitis
— Pneumocystis carinii pneumonia
This must be differentiated from other intrauterine infections that have similar manifestations in the newborn, and from other conditions that cause retinal lesions. These include:
— Herpes simplex virus
— Lymphocytic choriomeningitis virus syndrome
— Congenital retinal anomalies
— Congenital hypertrophy of the retinal pigmented epithelium
What caused this disease to develop at this time?
Toxoplasma gondii is ubiquitous in the environment in the form of oocysts shed from the intestines of acutely infected felines. Millions of oocysts are shed each day in the feces for up to 3 weeks.
The oocysts contaminate sand, soil, grass, and gardens in any location where felines live or visit, including private yards, fields, parks, farmland, and outdoor recreational facilities.
Outdoor water sources, sand boxes, fresh garden produce, and, of course, cat litter boxes may be contaminated.
Many warm blooded animals, including humans, may become infected after inadvertently ingesting oocysts.
Adults and children may ingest sufficient oocysts by autoinoculation after their hands are contaminated during outdoor activities:
Handling (or eating) fresh, unwashed produce
Handling/cleaning cat litter
Drinking from contaminated outdoor water sources
Playing in sand boxes
Livestock and other farm animals may ingest oocysts and become chronically infected with Toxoplasma living in microscopic tissue cysts in many organs, including skeletal muscle.
Human consumption of undercooked meat may result in acute Toxoplasma infection.
Pork and mutton have been particularly identified as sources in the past, but beef has also been infected, and an outbreak of toxoplasmosis has occurred in association with hamburger.
Handling raw meat can result in contamination of hands and subsequent autoinoculation.
Contaminated cutting boards and utensils are also potential sources if not cleaned after use with raw meat or oocyst -contaminated fresh, unwashed produce.
Other potential exposures:
Rarely, blood may be donated during the parasitemia stage in an acutely infected, healthy donor.
Acute toxoplasmosis following blood transfusion has been reported.
Solid organs donated from previously infected individuals
Transplantation into immunosuppressed recipients has resulted in severe focal and disseminated toxoplasmosis.
Toxoplasmosis occurs throughout the world, but seropositive rates differ greatly in different regions.
High seroprevalence rates have been described for parts of Europe, South and Central Americas, and Central Africa.
Factors affecting prevalence rates include the primary mode of transmission (oocysts, tissue cysts, or mixed), which in turn depends on habitat, climate, and dietary habits.
Ingestion of oocysts may predominate in parts of the world with many outdoor-living cats and a warm, humid environment.
Seropositivity may begin in early infancy from playing in contaminated sand.
Consumption of undercooked meat appears to be the primary mode of transmission in some regions.
Seropositivity may not begin until later childhood or adolescence and continue throughout adulthood.
In many parts of the world, the transmission pattern is mixed.
Risk of infection depends on the yearly seroconversion rate for women of childbearing age.
Regions with high seroprevalence may have fewer women at risk for acute infection, but the yearly seroconversion rate may also be high, placing susceptible women at significant risk during pregnancy.
Seroprevalence rates among women of childbearing age in Europe varies between approximately 10% and 70%.
Seroprevalence rates among women of childbearing age in the United States are reported to be approximately 15%.
Studies in parts of the United States have indicated an incidence of congenital infection of 1 per 10,000 live births.
What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
Toxoplasma-specific serology and polymerase chain reaction (PCR) are, in most cases, the principal means of diagnosing T. gondii infection. There are a number of assays that have been developed that not only aid in the confirmation of infection, but are also helpful in distinguishing remote from acute infection.
Many tests are only available in reference laboratories, and even when provided in commercial laboratories, confirmation of results should be done through reference laboratory testing. In the United States, the reference laboratory is the Toxoplasma Serology Laboratory, Palo Alto Medical Foundation Research Institute, Palo Alto, CA (650-853-4828; http://www.pamf.org/serology).
Sabin-Feldman dye test
Uses live Toxoplasma tachyzoites maintained in the laboratory
Relies on the uptake of methylene blue dye by live organisms, and the loss of the dye from cells lysed in the presence of specific antibody and complement
Very useful in antenatal maternal screening
Positive dye titer very early in pregnancy signifies infection prior to conception.
Enzyme-linked immunosorbent assay (ELISA)
IgG-ELISA: Provides confirmation of infection, but this test is of limited value in the diagnosis of acute infection, reactivated disease in immunocompromised patients, or infection in the newborn, as it may only reflect maternal transplacental IgG.
IgM-ELISA: Only the double-sandwich Toxoplasma-specific IgM-ELISA has acceptable specificity
Should be performed in a reference laboratory where sensitivity well established
IgM titers may remain elevated from months to more than 1 year in the absence of anti-Toxoplasma treatment.
Titers may rebound post treatment, especially in infants
Very useful in determining congenital infection, as IgM does not cross the placenta
IgA-ELISA: Toxoplasma-specific IgA rises very early in infection, and high titers correlate with recent infection
May be useful in diagnosing congenital infection (IgA does not cross the placenta, nor is it likely to be absorbed from breast milk)
IgE-ELISA: Titers rise and fall faster than IgM or IgA, so this assay may be helpful in diagnosing acute infection.
IgG Avidity: This is a measure of the ease of dissociation of IgG-antigen complexes.
High avidity levels are consistent with acute infection having occurred at least 3 months past; however, the absence of high avidity levels does not confirm acute infection.
ISAGA: Serum titers are measured by agglutination of Toxoplasma antigen particles.
Very sensitive technique developed for both IgM and IgE
Complementary to ELISA assays
Differential Agglutination Test: Ratio of titers against formalin-fixed tachyzoites (“HS antigen”) relative to titers against acetone- or methanol-fixed tachyzoites (“AC antigen”)
Titer ratio reflects recent versus remote infection, as antibodies against the antigens displayed by the different fixation methods occur at different times in infection
PCR Amplification: May be performed on blood, CSF, amniotic fluid and vitreous fluid
Essentially 100% specificity and sensitivity when test specimens are properly processed and testing is performed in a reference laboratory
Test of choice for diagnosing fetal infection (amniotic fluid)
Useful in diagnosing Toxoplasma encephalitis in AIDS patients
Other assays have been developed but have either been supplanted by the above tests, or have been used primarily in research studies.
The interpretation of serology results may be difficult, and consultation with an infectious disease specialist and the reference laboratory should be obtained.
As for all cases of serological diagnosis of congenital infection, maternal serology should also be obtained along with newborn serology. When clinical suspicion for Toxoplasma infection is high in newborn infants or immunocompromised individuals, additional testing should be undertaken before serology results have returned. This is particularly important for symptomatic immunocompromised patients because Toxoplasma infection may become rapidly fulminant.
Suspected congenital infection:
Pediatric ophthalmologic examination, CSF studies, and intracranial imaging should be performed.
Suspected infection in immunocompromised patients
Testing is typically focused on the clinical findings
CSF profile (with Toxoplasma-specific PCR)
Cranial CT with contrast or MRI
Chest radiograph (typically an interstitial pneumonitis pattern)
Would imaging studies be helpful? If so, which ones?
Imaging studies may play an important role in the diagnosis and management of Toxoplasma infections, particularly with congenital disease and cases of encephalitis.
Antenatal fetal ultrasound surveys may be helpful in the diagnosis of congenital Toxoplasma infection.
Most infected fetuses will not have easily detected abnormalities.
Fetal hydrocephalus and sometimes “shadowing” from intracranial calcifications may be seen.
In the absence of an antenatal Toxoplasma screening program, the presence of fetal hydrocephalus or suspected intracranial lesions should prompt maternal Toxoplasma serology testing for Toxoplasma.
Intracranial imaging is important in the evaluation of infants with suspected congenital Toxoplasma infection.
Cranial ultrasound can be used to assess ventricular size and identify focal calcified brain lesions, but head CT scan may be more sensitive in detecting small calcified lesions.
In cases of suspected infection, intracranial imaging may help support the diagnosis before serology testing is completed, and in some cases it may even be appropriate to initiate anti-Toxoplasma therapy before confirmation serology results are obtained.
Head MRI may be more sensitive than head CT scan
Contrast enhancing lesions may be seen in basal ganglia and the corticomedullary junction of the cerebral hemispheres.
Multiple lesions are common.
Sometimes a target-like ring-enhanced lesion can be seen and is thought to be pathognomonic.
If you are able to confirm that the patient has toxoplasmosis, what treatment should be initiated?
Highly active anti-Toxoplasma drugs are available for treating acute disease caused by primary or reactivated infection. With the exception of atovaquone, these drugs are active against the Toxoplasma tachyzoites, not bradyzoites contained in tissue cysts.
Combination therapy is always recommended.
Commonly used in drug regimens to treat toxoplasmosis in many clinical settings
Anti-metabolite that is active against T. gondii, but can impact host cells
Leucovorin (folinic acid) protects host cells.
Like pyrimethamine, commonly used in drug regimens to treat toxoplasmosis
Synergistic with pyrimethamine
Other trisulfapyrimidines have been used
Effective when used with pyrimethamine
Sometimes used as added treatment with pyrimethamine and sulfadiazine
Acceptable alternative to sulfadiazine when drug intolerance is present
More experience in treating ocular disease in older children and adults
Can be used as intraocular therapy
Used successfully in treating ocular disease in older children and adults
Used for prophylaxis against recurrent disease in immunocompromised patients
Has been used in combination regimens for acute toxoplasmosis
May prevent fetal infection when given to mothers with acute infection in pregnancy.
Is not approved for use in the United States, but is available through an Investigational New Drug (IND) treatment protocol
Not effective in treating fetal infection
Active against bradyzoites in tissue cysts
Limited use in pediatrics
Dosing and bioavailability have been problematic
Has been used with ocular disease
Has good uptake and tissue penetration
Has been used in ocular regimens
Limited use in pediatric therapy
Specific regimens and drug dosing
Pyrimethamine and sulfadiazine plus leucovorin (folinic acid)
Preferred drug regimen
Adolescents and adults
Pyrimethamine 50 – 100 mg twice daily for the first day, then 25 – 75 mg once daily
Sulfadiazine 1 – 1.5 g per dose four times daily
Leucovorin (folinic acid) 5 – 10 mg three times per week
Dose is increased as needed to prevent side effects of pyrimethamine
Continue for one week after pyrimethamine therapy completed
Clindamycin 300 – 600 mg per dose given four times daily
May be substituted in individuals intolerant or allergic to sulfadiazine
Infants and children
Pyrimethamine 2 mg/kg once daily for 2 days (maximum 50 mg), then 1 mg/kg once daily (maximum 25 mg)
Sulfadiazine 100 mg/kg/day divided into two doses
Leucovorin (folinic acid) 5 – 10 mg three times per week
Clindamycin 20 – 30 mg/kg/day divided into four doses
May be substituted in individuals intolerant or allergic to sulfadiazine
Treatment of acute toxoplasmosis in immunocompetent children and non-pregnant adolescents and adults
Infection is usually self-limited and no treatment is recommended.
In rare cases of pronounced clinical symptoms, combination therapy with pyrimethamine and sulfadiazine plus folinic acid can be used.
Treatment is continued until clinical symptoms resolve (usually 2 to 6 weeks).
Treatment is typically continued until 2 weeks after resolution of acute inflammation
Prednisone is often added until acute inflammation resolved.
Treatment is typically for 6 weeks or until there is resolution of MRI changes
Corticosteroid therapy is often added for substantial mass effect or if there is a high CSF protein (>1000 mg/dL)
Treatment of acute toxoplasmosis in immunocompromised individuals
Combination therapy with pyrimethamine and sulfadiazine plus leucovorin is the preferred regimen.
Clindamycin may be substituted in cases of sulfadiazine hypersensitivity.
Therapy is continued until symptoms resolve.
Ocular disease and encephalitis are treated as for immunocompetent patients, except longer therapy may be required.
Encephalitis may also require extended therapy (>6 weeks) dependent of clinical symptoms and follow-up MRI imaging.
Special considerations–AIDS patients
Primary prophylaxis against Toxoplasma encephalitis in AIDS patients
TMP-SMX is used for primary prophylaxis
Adolescents and adults: 1 double-strength TMP-SMX tablet once daily
Children: (150 mg TMP/750 mg SMX)/m2/day divided into two doses daily
Prophylaxis is given to individuals with serology consistent with prior Toxoplasma infection
For children under 6 years, prophylaxis is given when CD4 counts are <15%
For children 6 years and over, and adolescents/adults, the cutoff is <100 cells/mm3
Prophylaxis against recurrent Toxoplasma encephalitis in AIDS patients
Pyrimethamine, sulfadiazine and folinic acid should be continued after symptoms have resolved
Current anti-retroviral therapy has significantly altered the need for prophylaxis, and once CD4 counts have risen above 200 cells/mm3 (≥6 years – adults) or ≥15% (<6 years) and have remained elevated for 3 months or more, prophylaxis may be discontinued
For patients who had encephalitis, prophylaxis should be continued for 6 months following resolution of disease before discontinuation following 3 months of immune reconstitution with effective anti-retroviral therapy.
Prophylaxis against fetal infection
Spiramycin 1 g three times daily should be given to pregnant women diagnosed with acute Toxoplasma infection.
Prompt initiation of therapy may reduce the risk of fetal infection.
Even if it is uncertain when maternal infection occurred, spiramycin should be used until the fetus can be further evaluated for infection.
There is normally a delay in fetal transmission following maternal parasitemia, so there still may be a benefit from spiramycin prophylaxis.
In the United States. the Toxoplasma Reference Laboratory at the Palo Alto Medical Foundation Research Institute should be consulted.
If maternal infection is confirmed, the Food and Drug Administration will release spiramycin under a treatment IND and the drug supplier will ship it overnight so therapy can be initiated.
Treatment of fetal infection
Amniocentesis is performed for Toxoplasma-specific PCR.
The specimen should be sent to a reference laboratory for testing.
It is important to obtain a sufficient volume of fluid and to process the specimen correctly.
Consult the reference laboratory for proper sampling and processing instructions.
If fetal infection is confirmed, spiramycin is discontinued and maternal pyrimethamine, sulfadiazine, and leucovorin are started.
Treatment should continue throughout the remainder of the pregnancy.
The newborn should undergo routine physical examination as well as ophthalmologic and CNS evaluations, and combination anti-Toxoplasma treatment should be continued.
If maternal infection is first diagnosed in later gestation, it may be reasonable to forgo spiramycin and go straight to pyrimethamine-sulfadiazine-leocovorin, especially if amniocentesis cannot be performed.
These drugs have potential toxicities that must be monitored.
It is preferable to perform amniocentesis and PCR to document fetal infection.
Treatment of the newborn with congenital Toxoplasma infection
A full evaluation should include:
Pediatric ophthalmology examination
Intracranial imaging (head CT)
Baseline CSF profile and Toxoplasma-specific PCR
Baseline hearing screen
Baseline neurology assessment
Baseline Toxoplasma-specific IgG and IgM (if not already available as part of the initial diagnosis)
Baseline serum BUN and creatinine, liver function tests
Baseline hematologic studies: CBC with differential, screen for glucose-6-phosphate dehydrogenase (G-6-PD) deficiency
Sulfadiazine, and to a lesser extent, pyrimethamine may trigger hemolytic disease in G-6-PD deficient infants.
Treat with pyrimethamine-sulfadiazine-leucovorin for 1 year
Pyrimethamine is given daily for 2 to 6 months, then every other day (same 1 mg/kg dose) for the remaining 6 to 10 months.
Sulfadiazine is continued twice daily for the entire 12 months.
CBC with differential is obtained every 1 to 2 weeks until stable, then every 2 to 4 weeks thereafter to monitor for bone marrow suppression.
The goal of therapy is to kill any active tachyzoites and suppress reactivation from tissue bradyzoites until the infant is likely to have better immunologic control of infection.
Periodic serology may be useful to monitor changes in therapy.
Typically, IgM titers fall and become negative on treatment.
It is particularly useful to obtain serologies at the end of treatment, then repeat them one month off treatment.
IgM often shows a rebound titer, but this does not appear to indicate any significant disease reactivation.
Ophthalmologic examination is useful at the same time to confirm no new ocular disease.
It is common to continue periodic neurologic and ophthalmologic follow-up.
Neurologic follow-up is usually 6 to 12 months apart. Ophthalmology examinations are performed 1 month off treatment, then every 3 to 6 months until the child can report visual change.
What are the adverse effects associated with each treatment option?
Adverse drug reactions may be seen with anti-Toxoplasma therapy, but in the absence of rare, severe reactions, most infants tolerate pyrimethamine and sulfadiazine very well.
The most common side effects are seen as hematologic abnormalities:
Neutropenia and anemia, usually due to pyrimethamine therapy
Pyrimethamine inhibits dihydrofolate reductase, preventing the production of folinic acid, a required cofactor for both host cell and T. gondii metabolism
The effect on host cells can usually be reversed by provision of exogenous folinic acid (leucovorin).
T. gondii has defective uptake of exogenous folinic acid, so is dependent on de novo synthesis.
Complete blood count (CBC) is monitored as a marker of the anti-metabolite effects of pyrimethamine. If the absolute neutrophil count (ANC) falls to under 1000 cells/mm3, increase the leucovorin dose
Obtain a follow-up CBC weekly and continue to adjust leucovorin until counts are stable above 1000 cells/mm3.
Initially increase leucovorin from 3 times per week to daily.
If neutropenia persists despite treatment with 10 mg or higher of leucovorin daily, consider sulfadiazine toxicity.
Neutropenia may be cyclical; therefore, a single low neutrophil count may not reflect drug-related bone marrow suppression.
It is still preferable to increase leucovorin rather than risk risk pyrimethamine suppression of metabolism.
Anemia may be difficult to separate from the physiologic nadir experienced by infants in the first 1 to 2 months after birth.
A sustained low hematocrit (below 25% to 30%) without appropriate reticulocytosis should be considered as drug-related.
In addition to supplemental dietary iron, leucovorin should be increased, as done for neutropenia.
Allergy to sulfadiazine is the more common reason for needing to replace this therapy, usually with clindamycin.
Sulfadiazine may also trigger hemolysis in patients with G-6-PD deficiency, so screening for this is important.
If G-6-PD deficiency is identified, clindamycin may be substituted.
Pyrimethamine may also trigger hemolysis in G-6-PD deficient patients, but this is less common.
Pyrimethamine therapy can be used with careful monitoring for a hemolytic event.
Sulfadiazine may prolong the half-life of phenytoin (elevation of level via interference with hepatic microsomal enzymes), so phenytoin dosing adjustments may be required.
Bone marrow suppression may be exacerbated in patients receiving carbamazepine, clonazepam, or zidovudine.
What are the possible outcomes of toxoplasmosis?
In non-pregnant immunocompetent patients, the prognosis following acute toxoplasmosis is excellent. Even in the rare cases of symptomatic infection, therapy is very effective against the active infection, and immunity develops rapidly with clearing of organisms not protected in tissue cysts.
There may be periodic rupture of tissue cysts, but the exposed organisms are rapidly killed by the immune response. There is, however, a risk of permanent visual impairment in the cases of acquired Toxoplasma ocular disease, but prompt recognition and treatment when an individual presents with acute visual changes or other ocular symptoms may preserve vision with minimal change. The key to successful treatment is the recognition that T. gondii is the principal cause of retinitis in children.
In immunocompromised patients, once treatment is underway and the patient is stable, long-term outcomes are harder to predict, but are generally good. Severe brain injury may occur with severe Toxoplasma encephalitis, but this disease is very uncommon in children, including those with AIDS. In addition, when access to effective anti-retroviral therapy is available, the immune function of HIV-infected patients can be maintained above the level at which acute Toxoplasma infection is unlikely to produce severe disease.
In general, congenital toxoplasmosis poses the greatest challenge, beginning with acute maternal infection. Since most pregnant women go undiagnosed when acquiring acute Toxoplasma infection during pregnancy, those with first trimester infection are at greatest risk for delivering a severely affected newborn.
Prevention and treatment of fetal infection with maternal acute Toxoplasma infection in pregnancy
Prompt recognition of acute maternal Toxoplasma infection, followed by initiation of anti-Toxoplasma therapy, may have a significant impact on the incidence and severity of fetal infection. In general, this requires repeated antenatal serological screening to identify women at risk for acute infection (seronegative at first testing) and determining if and when seroconversion may occur.
In the absence of serial screening, maternal infection is more often identified when symptoms are present. Most often, this may be a persistent lymphadenopathy that either prompts Toxoplasma serology to be performed or a lymph node excisional biopsy with histopathology. Thorough review of maternal symptoms may help identify when the infection started, and serology performed in a Toxoplasma reference laboratory may further help identify the likely timing of infection during pregnancy.
Once maternal infection has been confirmed, treatment with spiramycin is typically initiated pending further evaluation for fetal infection. A prospective controlled study in France showed a reduction in the rate of fetal infection from 58% to 23% when serial serological screening and prompt initiation of therapy were performed. Results from other centers have not shown this benefit, possibly due to delays in diagnosis and the start of treatment.
Most infected fetuses will not have ultrasound changes, so Toxoplasma-specific PCR has become a standard method to diagnose fetal infection. One study in France reported that 37 of 38 fetal infections were correctly identified by amniotic fluid PCR from 339 at-risk fetuses tested. The specificity was 100%. However, this degree of accuracy has not been found in all studies, including a multicenter European study that showed 48/75 infected fetuses to be correctly identified. Again, the specificity was 100%.
Once fetal infection is established by PCR testing, antenatal therapy is changed to pyrimethamine and sulfadiazine plus leucovorin. In France, pregnancy termination has historically been chosen at a significant rate when fetal Toxoplasma infection has been identified, but the approach of universal screening and treating acutely infected mothers has resulted in very favorable newborn outcomes.
Given the relatively low risk of severe fetal disease (low rate of first trimester transmission), the approach of treating a mother identified as having acute Toxoplasma infection in pregnancy may be expected to result in a good delivery outcome. This is especially true if the timing of infection can be further identified, through history and special serologies, as likely occurring in the second trimester or later. When the timing of maternal infection is less well established, the outcome is harder to predict.
Missed or delayed diagnosis of acute maternal infections, and the low, but potentially devastating outcome for untreated fetal infection occurring in early pregnancy, argue for antenatal screening programs that utilize prompt antenatal treatment.
Outcomes for newborns with subclinical or mild disease treated with extended drug regimens
Infants with subclinical or mild Toxoplasma disease at birth are at significant risk for long-term ocular and neurological sequelae, but one-year combination treatment regimens appear to significantly impact these long-term complications.
In the New England Toxoplasma Screening Program, 48 infants with subclinical or mild disease at birth were treated for one year with combination anti-Toxoplasma therapy. These infants all had normal growth and development with no hearing loss and only a 10% incidence of new-onset ocular disease.
Detailed evaluation and close monitoring of infants treated for one year in the National Collaborative Chicago-Based, Congenital Toxoplasmosis Study also demonstrated that, among the infants without substantial neurologic disease at birth who were treated with pyrimethamine and sulfadiazine for 1 year, all had normal cognitive, neurologic, and auditory outcomes, with only 9% developing new eye lesions. For infants with moderate or severe neurologic disease, none had hearing loss, >72% had normal neurologic and/or cognitive outcomes, and 36% developed new eye lesions.
Whether or not fetal treatment has been provided, all infants with congenital Toxoplasma infection should be treated for 1 year with pyrimethamine, sulfadiazine and leucovorin. The regimen is intense, with drugs administered each day and frequent blood count monitoring to check for bone marrow suppression; however, the drug regimen is tolerated very well and the potential benefit for all infants is well supported.
What causes this disease and how frequent is it?
Life Cycle and Transmission of Infection
Toxoplasma has both a sexual life cycle, dependent on felines (definitive host), and an asexual life cycle that occurs in many warm blooded animals (intermediate hosts), including humans.
Three forms of Toxoplasmaparticipate in different stages of infection:
Oocysts, containing sporozoites shed in feline feces (contaminating soil and grass)
Tachyzoites, a rapidly growing form producing parasitemia
Bradyzoites, a slow growing form encased in microscopic tissue cysts formed in many host organs following parasitemia
Transmission occurs as follows:
Oocysts, prey withtissue cysts ingested by felines → Oocysts formed in intestinal enterocytes → shed in feces
Oocysts ingested by intermediate host → Cysts rupture and sporozoites released → Tachyzoites form and spread from lymph node → Parasitemia →
Parasitemia → Spread to organs (including muscle, eye, brain, heart, lungs) → Subclinical or clinically apparent disease and tissue cysts →
Tissue cysts ingested by intermediate host → Cysts rupture, tachyzoites form/spread (parasitemia) → tissue cysts (intermediate host) →
Cycle continues with oocysts, tissue cysts → tissue cysts (intermediate host) or oocysts (felines)
Occurs via vertical transmission from mother to fetus
Requires acute maternal infection during pregnancy
Reactivation of infection remote to pregnancy may occur in immunosuppressed mothers.
Tachyzoites (maternal parasitemia) spread to fetus via placenta
Risk of infection correlates with placental efficiency.
Transmission rates increase at increasing gestational age, ranging from as low as 1% or less in the peri-conceptional period to as high as 90% or greater at term.
Reported transmission rates vary somewhat among studies, but there is essentially a doubling of fetal risk per trimester following acute maternal infection.
Conversely, the severity of congenital toxoplasmosis correlates inversely with gestational age, with most cases of severe disease resulting from first trimester infection (Table II).
|Trimester when acute maternal infection occurred|
|Risk of fetal infection (%)||15||30||60|
|Severity of fetal disease (%)|
|Stillbirths or perinatal deaths (%)||35||7||
Fetal infection rarely has been reported if a mother is infected prior to pregnancy, unless she is immunocompromised and at risk for systemic spread of Toxoplasma from reactivated chronic infection. Symptoms of reactivated maternal toxoplasmosis may be absent, and the risk of fetal transmission as a function of the degree of maternal immunosuppression is not known.
How do these pathogens/genes/exposures cause the disease?
General considerations for the pathogenesis of T. gondii infections
Toxoplasma gondii invades many cells in many tissues, resulting in direct cell injury.
Toxoplasma-specific IgG and IgM often rise by 1 week, and the parasitemia is cleared by that time.
Both host and strain factors determine the extent of tissue injury.
The primary host variable is the competency of the immune response, which is likely to be the principal reason for fetal, newborn and young infant susceptibility to progressive disease.
The immune response to parasitemia and local tissue injury determine, in part, the extent of inflammation following acute infection.
Strain virulence, size of inoculum, stage of parasite, and route of infection are important parasite variables.
Phylogenetic and statistical analyses indicate that T. gondii consists of three clonal lineages.
A relatively highly virulent T. gondii strain may be part of the high seroprevalence rates noted in Brazil.
There is also an unusually high incidence of ocular disease in the general population in Brazil, further suggesting an unusual host-parasite interaction in that region.
In most healthy children and adults, acute Toxoplasma infection is self-limited, with very focal tissue injury and inflammatory response.
Some individuals have more severe disease despite apparently normal immunity.
Studies in animal models have indicated that differences in genetic background may be associated with differences in susceptibility.
Tissue cysts appear to be composed of both Toxoplasma-specific and host cell components.
The resultant cyst may be “hidden” from the immune system.
Rupture of tissue cysts typically immediately triggers an immune response.
Some experts have argued that during extended treatment regimens for congenital Toxoplasma infection, it may be beneficial to alternate combination therapy with less active single therapy or even to interrupt continuous therapy with every other month off all treatment in order to stimulate the immune response. In the absence of comparison treatment data, it is preferable not to use this approach, but rather, use combination therapy throughout the entire one-year treatment course.
How can toxoplasmosis be prevented?
Although T. gondii is prevalent in many environments, simple measures may reduce the risk of acute infection. This is particularly important for women of childbearing age.
Keep cats indoors and empty litter daily
Oocysts take 24 hours to sporulate and become infectious
Women of childbearing age should avoid contact with litter if possible and if not, gloves should be worn during pregnancy.
Feed cats dry/canned/cooked food
Vaccinate when vaccine is available
Avoid eating undercooked meat.
Wear gloves and wash hands when handling uncooked meat.
Keep cutting boards and utensils clean between uses.
Wear gloves when gardening,
Wash hands thoroughly before eating.
Wear gloves and wash hands when handling fresh produce.
Freezing meat at -20°C kills the tissue cysts, so this may be helpful if done before unwrapping and handling meat.
Meat should be cooked to an internal temperature of 66°C (150°F) to kill tissue cysts.
All pregnant women should be counseled about the risk of congenital Toxoplasma infection and the above preventive steps.
In European countries with very high seroprevalence rates, aggressive antenatal screening and national prevention programs appear to have resulted in a decline in the incidence of congenital Toxoplasma infection.
What is the evidence?
Dubey, JP, Jones, JL. “Toxoplasma gondii infection in humans and animals in the United States”. Int J Parasitol. vol. 38. 2008. pp. 1257-78. (This article by Dubey and Jones provides an excellent discussion on modes of transmission, epidemiology and environmental contamination with oocysts, clinical and asymptomatic Toxoplasma gondii infection in humans and other animals, and the declining seroprevalence in humans and pigs in the United States.)
Remington, JS, McLeod, R, Wilson, CB, Desmonts, G, Remington, JS, Klein, JO, Wilson, CB, Nizet, V. “Toxoplasmosis”. 2011. pp. 918-1041. (This chapter on toxoplasmosis is comprehensive in providing an excellent general reference for the pathogenesis, seroprevalence, transmission, diagnosis, and treatment of Toxoplasma infections.)
Eichenwald, HF, Siim, JC. “A study of congenital toxoplasmosis with particular emphasis on clinical manifestations, sequelae and therapy”. 1959. (This classic study by Eichenwald provides an excellent description of the clinical findings in children with symptomatic, untreated toxoplasmosis.)
Wilson, CB, Remington, JS, Stagno, S, Reynolds, DW. “Development of adverse sequelae in children born with subclinical congenital Toxoplasma infection”. Pediatrics. vol. 66. 1980. pp. 767-74.
Koppe, JG, Loewer-Sieger, DH, de Roever-Bonnet, H. “Results of 20-year follow-up of congenital toxoplasmosis”. Lancet. vol. 1. 1986. pp. 254-6.
Sever, JL, Ellenberg, JH, Ley, AC. “Toxoplasmosis: maternal and pediatric findings in 23,000 pregnancies”. Pediatrics. vol. 82. 1988. pp. 181-92. (The above 3 articles by Wilson, Koppe, and Sever and their collaborators are frequently referenced for the risk of late sequelae of neurologic, ocular, and hearing deficits found in infants with congenital Toxoplasma infection who were untreated, or minimally treated with anti-Toxoplasma drugs.)
Guerina, NG, Hsu, HW, Meissner, HC. “Neonatal serologic screening and early treatment for congenital Toxoplasma gondii infection. The New England Regional Toxoplasma Working Group”. N Engl J Med. vol. 330. 1994. pp. 1858-63.
McLeod, R, Boyer, K, Karrison, T. “Outcome of treatment for congenital toxoplasmosis, 1981-2004: the National Collaborative Chicago-Based, Congenital Toxoplasmosis Study”. Clin Infect Dis. vol. 42. 2006. pp. 1383-94. (The above 2 articles by McLeod and Guerina and their collaborators present outcome data for infants treated for one year for congenital Toxoplasma infection. There are no randomized studies of treatment versus no treatment, but the incidence of late sequelae is significantly lower than expected, especially when compared with that of untreated infants in the previous 3 studies.)
Montoya, JG, Remington, JS. “Management of Toxoplasma gondii infection during pregnancy”. Clin Infect Dis. vol. 47. 2008. pp. 554-66. (This review by Montoya and Remington provides an excellent summary on serological testing and the approach to treatment of T. gondii infections in various clinical situations.)
Mofenson, LM, Brady, MT, Danner, SP. “Guidelines for the Prevention and Treatment of Opportunistic Infections among HIV-exposed and HIV-infected Children: Recommendations from CDC, the National Institutes of Health, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics”. MMWR Recomm Rep. vol. 58. 2009. pp. 1-166. (This MMWR report by Mofenson and colleagues provides an excellent discussion on opportunistic infections in HIV-exposed and infected children, and includes a summary on the presentation and treatment of Toxoplasma encephalitis.)
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- OVERVIEW: What every practitioner needs to know
- Are you sure your patient has Toxoplasma gondii infection? What are the typical findings for this disease?
- What other disease/condition shares some of these symptoms?
- What caused this disease to develop at this time?
- What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
- Would imaging studies be helpful? If so, which ones?
- If you are able to confirm that the patient has toxoplasmosis, what treatment should be initiated?
- What are the adverse effects associated with each treatment option?
- What are the possible outcomes of toxoplasmosis?
- What causes this disease and how frequent is it?
- How do these pathogens/genes/exposures cause the disease?
- How can toxoplasmosis be prevented?
- What is the evidence?