AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• Multimedia
• References

Background

Toxoplasma gondii is an intracellular parasite that affects one third of the world’s population.¹¹ It can affect all mammals who serve as the intermediate host. Cats are the definitive hosts. Toxoplasma may transmitted via hand-to-mouth contact from improper handling of, or ingestion, of raw or undercooked meat containing cysts from cat feces; by congenital transmission from mother to fetus; and rarely by transplantation of infected organs. The life cycle of Toxoplasma species includes tissue cysts in neural (mostly brain) and muscular (mostly skeletal and cardiac) tissue and fecal oocysts within the GI tract. Either may transform after ingestion and become infective over a period of several days.

Acute infection in an immune-competent host usually causes a self-limited, flulike illness. The situation is very different for the fetus or for an individual who is immune compromised due to human immunodeficiency virus (HIV), immune-suppressant drugs, or other illness. Fulminant infection with significant morbidity and mortality or ongoing low-grade symptoms is possible in these populations.

Pathophysiology

T gondii exists in 3 forms: oocysts, tachyzoites, and cysts.

Oocysts

Oocytes exist in cats—the definitive hosts. During acute infection in the cat, millions of oocytes are produced and shed in the cat’s feces for 7-21 days. These sporozoite-containing oocytes transform and become infectious after ingestion.

Tachyzoites

Tachyzoites are the rapidly replicating form of the parasite that occur inside the body of the intermediate host. They can actively penetrate all nucleated cells and form vacuoles. Eventually, the infected cells die and tachyzoites disseminate throughout the body to infect and destroy other tissues including the eye, CNS, skeletal and heart muscle, and placenta. They also cause an inflammatory response. In an immunocompetent host, the tachyzoites transform into bradyzoites, which form cysts.

Cysts

Bradyzoites remain in cysts for the life of the host in the host brain, heart, and skeletal muscle. They can be released from the cyst to transform back into tachyzoites to infect other tissues in immunocompromised hosts. Bradyzoites are morphologically similar to tachyzoites but are much slower replicating.

Human infestation

Humans can become infected with T gondii by ingesting either material contaminated with infectious oocysts or tissue cysts contained in raw or undercooked meat from another intermediate host. T gondii also may be transmitted by transplantation of infected organs, through blood transfusion, and through laboratory accidents. Transplacental transmission of T gondii is the only form of human-to-human transmission of toxoplasmosis. The rate of transplacental transmission has been reported to be 55% for untreated mothers and 25% for treated mothers.

Most cases of toxoplasmosis in the immunocompetent host are subclinical or benign. The most severe symptoms occur in the congenitally acquired form and in immunocompromised hosts. In the immunocompetent host, toxoplasmosis is classified as congenital, acquired, or ocular.

Approximately 10-20% of pregnant women infected with T gondii show clinical signs. The most common finding is lymphadenopathy. If the mother was infected prior to the current pregnancy, virtually no risk of fetal transmission exists. If the mother becomes infected during pregnancy, the fetus is at risk regardless of whether the mother is symptomatic. Fetal infection with T gondii may result in stillbirth or abortion. Congenital infection is most severe if acquired in the first or, in some cases, second trimester. Infection during the second or third trimesters tends to be asymptomatic. Seventy-five percent of infants born with congenital toxoplasmosis infection are asymptomatic. Eight percent show severe CNS impairment, which might not manifest for several years.

Patients with acquired toxoplasmosis can present with a range of clinical manifestations, from subclinical lymphadenopathy (the most common presentation) to fatal, fulminant disease. In the immunocompetent host, infection with T gondii may be indistinguishable from infectious mononucleosis.

Ocular toxoplasmosis occurs from activation of cysts deposited in or near the retina (see Media file 1). Focal necrotizing retinitis is the characteristic lesion. Approximately 35% of all cases of retinochoroiditis can be attributed to toxoplasmosis. Since most cases of ocular toxoplasmosis are the result of congenital infection, clinical manifestation later in life usually represents reactivation of latent infection.

The most severe forms of toxoplasmosis occur in patients who are immunocompromised. Immunocompromised hosts at risk include patients with malignancies, leukemias, collagen-vascular diseases, or acquired immunodeficiency syndrome (AIDS) and organ-transplant recipients. Clinical toxoplasmosis occurs in as many as 40% of patients with AIDS. Clinical toxoplasmosis usually is due to reactivation of latent T gondii infection; therefore, all patients with AIDS with T gondii antibodies are at risk of developing active infection.

Clinical manifestations may mimic those of other opportunistic infections. Necrotizing encephalitis, pneumonitis, and myocarditis are the most common autopsy findings. The most frequent clinical findings reflect involvement of these 3 organ systems, although disseminated toxoplasmosis is being described with increasing frequency. Incidence of toxoplasmic encephalitis in patients with AIDS is correlated directly with the presence of antitoxoplasmal antibodies. In patients with AIDS, CNS involvement is the most common manifestation, ranging from nonspecific, generalized symptoms to focal findings such as headache, altered levels of consciousness, motor impairment, and seizures.

Pulmonary involvement is the second most common manifestation. Clinically, patients may appear to have tuberculosis or infection with Pneumocystis carinii.

Frequency

United States

Toxoplasmosis is the third most fatal food-borne disease in the United States. The overall all seroprevalence in the United States is estimated to be 22.5%. Fifteen percent of women aged 15-44 years are seropositive. Congenital toxoplasmosis is uncommon in the United States and is estimated to occur in 4004000 births per year or 1-10 births per 10,000 live births. Seroprevalence of T gondii varies among populations and correlates with eating and hygiene habits of each population.

International

In France and Germany, as many as 80% of the general population has serologic evidence of subclinical T gondii infection.

Mortality/Morbidity

In the United States, approximately 225,000 cases of toxoplasmosis occur per year, and 5000 hospitalizations and 750 deaths occur.

Race

No difference between races is reported.

Sex

Although toxoplasmosis is well studied in women of childbearing age because of its detrimental effects on the fetus, no difference in prevalence between the sexes is reported.

Age

No difference in seroprevalence by age is reported.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• Multimedia
• References

History

• Immunocompetent individuals
• • Usually asymptomatic
  • Nonspecific, flulike illness
• Ocular toxoplasmosis (chorioretinitis)
• • Usually painless
  • Impaired vision, either sudden or gradual
  • May see floaters  
• Immunocompromised individuals
• • May have flulike symptoms
  • Seizure, dysequilibrium, cranial nerve deficits, altered mental status, focal neurologic deficit
• Congenital toxoplasmosis
• • Petechia
  • Visual defects

Physical

• Immunocompetent individuals
• • Usually asymptomatic
  • Isolated cervical or occipital adenopathy, nontender, last 4-6 weeks
  • Infrequently, may cause myocarditis, polymyositis, pneumonitis, hepatitis, encephalitis 
• Ocular toxoplasmosis (chorioretinitis)
• • White focal lesions with inflammation of vitreous (the classic “headlight in the fog” appearance)
  • Recurrent lesions at the border of the chorioretinal scars
• Congenital toxoplasmosis
• • Usually normal prenatal sonogram
  • Prenatal sonogram may show intracranial calcifications, dilated ventricles, enlarged liver, ascites, and thickened placenta
  • Neonatal hydrocephalus, microcephaly, intracranial calcifications, chorioretinitis, strabismus, blindness, epilepsy, psychomotor or mental retardation, thrombocytopenia (petechia), anemia
  • Rare classic triad - Chorioretinitis, hydrocephalus, cerebral calcifications
• Immunocompromised individuals
• • May be gradual onset over a few weeks
  • May be present as sudden confusion manifesting over days
  • Neurologic signs may be present: Seizure, mental status change, focal motor deficits, cranial nerve disturbances, sensory disturbances, cerebellar abnormalities, movement disorders, neuropsychiatric findings
  • Chorioretinitis
  • Pneumonitis (more common in patients who have undergone bone marrow transplantation and in patients with AIDS)
  • Septic shock-like presentation

Causes

• Immunocompetent individuals - Oral-fecal acquisition of parasite from cat feces or eating contaminated, undercooked meat (especially pork and lamb)
• Ocular toxoplasmosis (chorioretinitis)
• • Usually reactivation of congenital infection
  • Few cases recorded as part of acute infection 
• Immunocompromised individuals - Almost always reactivation of chronic infection 
• Congenital toxoplasmosis
• • Parasite crosses the placenta from maternal circulation and then enters the fetus.
  • Infection is less frequent but more serious if mother becomes infected from up to 3 months before pregnancy until end of the second trimester.
  • Infections are more frequent but less severe if maternal infection occurs in the third trimester.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• Multimedia
• References

Other Problems to Be Considered

Other lesions caused by Cryptococcus neoformans, Aspergillus species, Mycobacterium tuberculosis, Nocardia species

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• Multimedia
• References

Lab Studies

• Indirect detection
• • Indirect detection is performed in pregnant women and immunocompromised patients.
  • Detection of immunoglobulin G (IgG) is possible within 2 weeks using enzyme-linked immunoassay (ELISA), IgG avidity test, and agglutination and differential agglutination test.
  • Immunoglobulin M (IgM) rises within the first week of infection. Negative detection essentially rules out the disease. However, the false-positive rate is 60%. 
• Direct detection
• • Polymerase chain reaction (PCR) amplification of T gondii gene is possible.
  • Tachyzoites may be demonstrated in tissues or smears. They also can be seen in CSF. CSF also shows mononuclear pleocytosis and elevated protein level.
  • Detection of tissue cysts confirms the diagnosis, but it does not differentiate between acute disease and chronic disease.
  • Brain biopsy is the definitive diagnosis.

Imaging Studies

• MRI is more sensitive than CT (and CT with contrast is more sensitive than without) for detecting brain lesions due to toxoplasmosis. One study showed that MRI detected abnormalities that influenced diagnosis and treatment of 40% of patients; those abnormalities were not detected on CT.
• A broad differential diagnosis remains in patients with abnormalities identified on CT or MRI.
• Single-photon computed tomography (SPECT) is useful in distinguishing between CNS lymphoma and infection (ie, toxoplasmosis or any other infection).

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• Multimedia
• References

Emergency Department Care

• Care of the patient in the ED should be specific to the presenting manifestations of the disease.
• Adequate airway, breathing, and circulation must be assessed and treated accordingly. 
• Adequate fluid resuscitation, pain control, and fever control must be ensured.
• Neuroimaging should be considered for an immunocompromised patient with new neurologic deficit, cranial nerve abnormality, or altered mental status.
• See Medication for medications regimens.

Consultations

Subspecialty consultation is required for the seriously ill patient, according to organ-specific involvement.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• Multimedia
• References

• Nonpregnant patients
• • Six-week regimen
  • Pyrimethamine (100 mg loading dose PO followed by 25-50 mg/d) plus sulfadiazine (2-4 g/d divided qid)

or

• Pyrimethamine (100 mg loading dose PO followed by 25-50 mg/d) plus clindamycin (300 mg PO qid)
• Folinic acid (10-25 mg/d) should be given to all patients to prevent hematologic toxicity of pyrimethamine.
• May substitute sulfadiazine or clindamycin for azithromycin 500 mg daily or atovaquone 750 mg bid in immunocompetent patients or patients with history of allergy to the former drugs
• Consider steroids in patients with radiologic midline shift, clinical deterioration after 48 hours, or elevated intracranial pressure.
• Pregnant patients
• • Spiramycin 1 g PO q8h
  • If amniotic fluid test result for T gondii is positive:
  • • 3 weeks of pyrimethamine (50 mg/d PO) and sulfadiazine (3 g/d PO in 2-3 divided doses) alternating with 3-week course of spiramycin 1 g tid

or

• Pyrimethamine (25 mg/d PO) and sulfadiazine (4 g/d PO) divided bid/qid until delivery

and

• Leucovorin 10-25 mg/d PO to prevent bone marrow suppression
• Patients with AIDS
• • Patients with AIDS are treated with pyrimethamine 200 mg PO initially, followed by 50-75 mg/d PO plus folinic acid 10 mg/d PO plus sulfadiazine 4-8 g/d PO for as long as 6 weeks, followed by lifelong suppressive therapy.
  • Suppressive therapy for patients with AIDS is pyrimethamine 50 mg/d PO plus sulfadiazine 1-1.5 g/d PO plus folinic acid 10 mg/d PO for life.

Drug Category: Anti-infectives

Empiric anti-infective therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Drug Name	Pyrimethamine (Daraprim)
Description	Folic acid antagonist that selectively inhibits plasmodial dihydrofolate reductase. Highly selective against plasmodia and T gondii. Does not destroy gametocytes but arrests sporogony in mosquito. Possesses blood schizonticidal and some tissue schizonticidal activity against malaria parasites of humans. Extend regimens to include suppressive cure through any characteristic periods of early recrudescence and late relapse for at least 6-10 wk in each case. Folinic acid should be given to all patients to prevent hematologic toxicity of pyrimethamine
Adult Dose	Nonpregnant patients: 100 mg loading dose PO followed by 25-50 mg/d plus either sulfadiazine 2-4 g/d PO divided qid, clindamycin 300 mg PO qid; may substitute azithromycin for 6 wk May substitute sulfadiazine or clindamycin for azithromycin 500 mg PO qd or atovaquone 750 mg PO bid in immunocompetent patients or patients with history of allergy to the former drugs Pregnant patients: 50 mg/d PO for 3 wk plus sulfadiazine alternating with 3-wk course of spiramycin 1 g tid or 25 mg/d PO and sulfadiazine 4 g/d PO divided bid/qid until delivery and leucovorin 10-25 mg/d PO to prevent bone marrow suppression
Pediatric Dose	1-2 mg/kg/d PO divided bid for 1-3 d initial; followed by 1 mg/kg/d bid for 4 wk; not to exceed 25 mg/d
Contraindications	Documented hypersensitivity; megaloblastic anemia resulting from folate deficiency
Interactions	Antifolic acids, such as methotrexate and pyrimethamine, may increase risk of bone marrow suppression; discontinue use if signs of folate deficiency develop; lorazepam may cause mild hepatotoxicity
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Exercise caution with hepatic or renal impairment; may precipitate hemolytic anemia with G-6-PD deficiency, generally in presence of other stressful events

Drug Name	Sulfadiazine (Microsulfon)
Description	Through competitive antagonism of PABA, interferes with microbial growth. Useful in treatment of toxoplasmosis.
Adult Dose	Nonpregnant patients: 2-4 g/d PO divided qid plus 100 mg pyrimethamine loading dose followed by 25-50 mg/d pyrimethamine Pregnant patients: 3 g/d PO divided bid/tid plus 50 mg/d pyrimethamine PO for 3 wk plus alternating with 3-wk course of spiramycin 1 g tid or 25 mg/d pyrimethamine PO and sulfadiazine 4 g/d PO divided bid/qid until delivery plus leucovorin 10-25 mg/d PO to prevent bone marrow suppression
Pediatric Dose	<2 months: Not recommended >2 months: 75 mg/kg or 2 g/m2 initial; followed by 150 mg/kg/d or 4 g/m2/d in 4-6 divided doses; not to exceed 6 g/d
Contraindications	Documented hypersensitivity
Interactions	May enhance anticoagulant action of warfarin; may enhance anesthetic effects of thiopental; may increase serum phenytoin levels; may decrease cyclosporine concentrations and increase risk of nephrotoxicity
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Caution with impaired renal or hepatic function, or G-6-PD deficiency; adjust dose with renal insufficiency

Drug Name	Clindamycin (Cleocin)
Description	As alternative to sulfonamides, may be beneficial when used in combination with pyrimethamine in acute treatment of CNS toxoplasmosis in patients with AIDS.
Adult Dose	Nonpregnant patients: 300 mg PO qid plus 100 mg pyrimethamine loading dose PO followed by 25-50 mg/d pyrimethamine
Pediatric Dose	8-16 mg/kg/d IV/IM divided tid/qid
Contraindications	Documented hypersensitivity; regional enteritis; ulcerative colitis; hepatic impairment; antibiotic-associated colitis
Interactions	Increases duration of neuromuscular blockade induced by tubocurarine and pancuronium; erythromycin may antagonize effects; antidiarrheals may delay absorption
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Adjust dose for severe hepatic dysfunction, but no adjustment needed for renal insufficiency; use associated with severe and possibly fatal colitis

Drug Name	Azithromycin (Zithromax)
Description	Acts by binding to 50S ribosomal subunit of susceptible microorganisms and blocks dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Nucleic acid synthesis is not affected. Concentrates in phagocytes and fibroblasts as demonstrated by in vitro incubation techniques. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues. Treats mild-to-moderate microbial infections. May substitute sulfadiazine or clindamycin for azithromycin in immunocompetent patients or patients with history of allergy to the former drugs
Adult Dose	500 mg PO qd for 6 wk Toxoplasmic encephalitis in patients with AIDS: 1200-1500 mg PO qd for 3-6 wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; hepatic impairment; do not administer with pimozide
Interactions	May increase toxicity of theophylline, warfarin, and digoxin; effects are reduced with coadministration of aluminum and/or magnesium antacids; nephrotoxicity and neurotoxicity may occur when coadministered with cyclosporine
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Site reactions can occur with IV route; bacterial or fungal overgrowth may result from prolonged antibiotic use; may increase hepatic enzymes and cholestatic jaundice; caution in patients with impaired hepatic function or prolonged QT intervals

Drug Name	Atovaquone (Mepron)
Description	A hydroxynaphthoquinone that inhibits mitochondrial electron transport chain by competing with ubiquinone at ubiquinone-cytochrome-c-reductase region (complex III). Inhibition of electron transport by atovaquone will result in inhibition of nucleic acid and ATP synthesis in parasites. Atovaquone has shown activity against bradyzoites in animal models of toxoplasmosis. May substitute sulfadiazine or clindamycin for atovaquone
Adult Dose	750 mg PO bid for 6 wk in nonpregnant immunocompetent patients or patients with history of allergy to alternative drugs
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	May increase zidovudine serum levels; coadministration with rifampin or rifabutin may decrease atovaquone levels; atovaquone may decrease levels of TMP-SMZ
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Caution in elderly persons and in hepatic and renal impairment

Drug Category: Antidote, Folic Acid Antagonist

These agents are used to replenish folic acid when the patient is being treated with folic acid antagonists.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• Multimedia
• References

Deterrence/Prevention

• Prevention of T gondii infection includes the following:
• • Thoroughly cooking all meat
  • Careful handwashing after handling raw meat
  • Washing fruits and vegetables before eating them
  • Pregnant women wearing gloves while gardening, thoroughly washing their hands afterwards, and avoiding contact with cat feces
• Development of vaccines for use in nonimmune women of childbearing age and household cats is being investigated.

Complications

• Seizures
• Partial or complete blindness
• Congenital complications
• • Mental retardation
• • Seizures
• • Deafness
• • Blindness

Prognosis

• Relapse is frequent with patients who are immunocompromised.

ACKNOWLEDGMENTS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• Multimedia
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Joseph Sciammarella, MD, to the development and writing of this article.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• Multimedia
• References

Media file 1:  Ophthalmic toxoplasmosis. Used with permission of Anton Drew, ophthalmic photographer, Adelaide, South Australia.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• Multimedia
• References

1. Garcia LS, Bruckner DA. Diagnostic Medical Parasitology. 111-121. 3^rd ed. American Society of Microbiology: Washington DC; 1997:423-424; 577-589.
2. Hardman JG, Limbird LE. Protozoal infections. In: Goodman LS, et al, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 9^th ed. New York: McGraw-Hill; 1992:989.
3. Hoeprich PD, Jordan MC, Ronald AR. Infectious Diseases. In: A Treatise of Infectious Processes. Lippincott-Raven Publishers; 1994:1201-1213.
4. Reese RE, Betts RF. A Practical Approach to Infectious Diseases. 648-649. Philadelphia, Pa: Little, Brown & Co; 1996:755-759; 1274-1275.
5. Robert-Gangneux F, Gavinet MF, Ancelle T, Raymond J, Tourte-Schaefer C, Dupouy-Camet J, et al. Value of prenatal diagnosis and early postnatal diagnosis of congenital toxoplasmosis: retrospective study of 110 cases. J Clin Microbiol. Sep 1999;37(9):2893-8. [Medline].
6. Sanford JP, Gilbert DN, Moellering RC. The Sanford Guide to Antimicrobial Therapy. Hyde Park, Vt: Antimicrobial Therapy, Inc; 1997:86-87.
7. Wong SY, Remington JS. Biology of Toxoplasma gondii. AIDS. Mar 1993;7(3):299-316. [Medline].
8. Buzoni-Gatel D, Werts C. Toxoplasma gondii and subversion of the immune system. Trends Parasitol. Oct 2006;22(10):448-52. [Medline].
9. Davaro RE, Thirumalai A. Life-threatening complications of HIV infection. J Intensive Care Med. Mar-Apr 2007;22(2):73-81. [Medline].
10. Dodds EM. Toxoplasmosis. Curr Opin Ophthalmol. Dec 2006;17(6):557-61. [Medline].
11. Montoya JG, Liesenfeld O. Toxoplasmosis. Lancet. Jun 12 2004;363(9425):1965-76. [Medline].

Article Last Updated: Dec 20, 2007