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Toxoplasmosis
Jonathan MacClements, MD, FAAFP
image BASICS
  • Toxoplasma gondii is an obligate intracellular protozoan parasite.
  • Most common latent protozoan infection
  • Clinically significant disease typically manifests only in pregnancy or in an immunocompromised patient.
DESCRIPTION
  • Acute self-limited infection in immunocompetent
  • Acute symptomatic or reactivated latent infection in immunocompromised persons
  • Congenital toxoplasmosis (acute primary infection during pregnancy)
  • Ocular toxoplasmosis
Pediatric Considerations
  • The earlier fetal infection occurs, the more severe.
  • Risk of perinatal death is 5% if infected in 1st trimester.
Pregnancy Considerations
  • Pregnant immunocompromised and HIV-infected women should undergo serologic testing.
  • Seronegative pregnant women should receive preventive counseling.
  • Serologic testing during pregnancy remains controversial.
EPIDEMIOLOGY
Incidence
  • Prevalence of congenital toxoplasmosis in the United States: 10 to 100/100,000 live births
  • Predominant sex: male > female
Prevalence
  • Present in every country. Seropositivity rates range from <10% to >90% (1)[A].
  • In the United States, 11% of individuals aged 6 to 49 years are seropositive. Age-adjusted prevalence in the United States is 22.5%.
  • Seroprevalence among women in the United States is 15%.
ETIOLOGY AND PATHOPHYSIOLOGY
Transmission to humans
  • Ingestion of raw or undercooked meat, food, or water containing tissue cysts or oocytes; usually from soil contaminated with feline feces
  • Transplacental passage from infected mother to fetus; risk of transmission is 30% on average.
  • Blood product transfusion and solid-organ transplantation
  • Ingested T. gondii oocysts enter host's gastrointestinal tract where bradyzoites/tachyzoites are released, penetrate contiguous cells, replicate and are transported to susceptible tissues where clinical disease manifests.
Genetics
Human leukocyte antigen (HLA) DQ3 is a genetic marker of susceptibility in AIDS.
RISK FACTORS
  • Immunocompromised states, including HIV infection with CD4 cell count <100/&mgr;L
  • Primary infection during pregnancy; risk of fetal transmission increases with gestational age at seroconversion. Transmission in the 1st trimester is associated with more severe consequences.
  • Chronically infected pregnant women who are immunocompromised have an increased risk of transmitting congenital toxoplasmosis.
GENERAL PREVENTION
Prevention is important in seronegative pregnant women and immunodeficient patients.
  • Avoid eating undercooked meat: Cook to 152°F (66°C) or freeze for 24 hours at ≤ - 12°C.
  • Avoid drinking unfiltered water.
  • Wash produce thoroughly.
  • Strict hand hygiene after touching soil
  • Wear gloves and wash hands after handling raw meat or cat litter.
  • Avoid shellfish (Toxoplasma cysts).
COMMONLY ASSOCIATED CONDITIONS
  • Chorioretinitis; self-limiting, febrile lymphadenopathy; mononucleosis-like illness
  • An unclear association exists between schizophrenia and several infectious agents including T. gondii.
image DIAGNOSIS
PHYSICAL EXAM
  • In adults: fever, lymphadenopathy, nonpruritic rash
  • In newborns: hydrocephalus, neurologic abnormalities, hepatosplenomegaly, chorioretinitis, microcephaly, mental retardation
DIFFERENTIAL DIAGNOSIS
Syphilis, lymphoma, progressive multifocal leukoencephalopathy, cryptococcal meningitis, congenital TORCH infections, Listeria infection, tuberculosis (TB), erythroblastosis fetalis
DIAGNOSTIC TESTS & INTERPRETATION
  • CBC: atypical lymphocytosis, anemia, thrombocytopenia
  • Serology interpretation
    • In acute infection, IgM antibodies appear within the 1st week.
    • Diagnosis can be made if initial test demonstrates positive IgM and negative IgG, with both tests being positive 2 weeks later.
    • If follow-up IgG remains negative 2 to 4 weeks later but IgM is still positive, it is likely a false positive.
    • Negative IgG rules out prior infection (IgG remains detectable for life).
  • Types of serologic tests
    • ELISA: most commonly used
    • Sabin-Feldman dye test: Gold standard against which all other serologic assays are compared.
    • IFA test: more available in commercial labs
    • ISAGA: widely available commercially; more sensitive and specific than IFA for detecting IgM
    • Avidity testing: confirmatory test to establish whether positive IgM/IgG reflects recent or chronic infection
  • PCR: T. gondii DNA amplification in blood or amniotic fluid; used for diagnosis of fetal infection
  • Culture (rarely necessary): Organism can be isolated either by cell culture or by mouse inoculation.
Initial Tests (lab, imaging)
  • Diagnosis of primary infection is typically based on history and confirmed by serology.
  • Serum Toxoplasma -specific IgG and IgM are first step.
  • According to the result of IgM test, determine IgG avidity.
  • Diagnosis of maternal infection and congenital toxoplasmosis
    • Pregnant women who have mononucleosis-like illness but negative heterophile test should be tested for toxoplasmosis.
    • Maternal infection accurately diagnosed when based on two blood samples at least 2 weeks apart showing seroconversion
    • High avidity of IgG during 1st trimester argues against maternal primary infection.
    • Real-time PCR analysis for T. gondii in amniotic fluid predicts fetal infection and helps guide appropriate treatment and surveillance.
    • Fetal ultrasound is useful for prognosis.
    • Routine screening for toxoplasmosis is not recommended.
  • Diagnosis of congenital toxoplasmosis after birth
    • Serology requires several serum samples for IgM and IgA antibodies.
    • Sampling of the cord or peripheral blood should be done within the first 2 weeks.
    • Ophthalmologic, auditory, and neurologic examinations; lumbar puncture; and head CT should be performed.
  • Diagnosis of toxoplasmic encephalitis
    • Serology for IgG
    • Imaging: MRI is more sensitive than CT scan for identification of characteristic ring-enhancing brain lesions.
  • P.1051

  • MRI: for identifying multiple ring-enhancing brain lesion in AIDS patients with cerebral toxoplasmosis
  • SPECT and PET scans: can help distinguish toxoplasmosis from CNS lymphoma
Diagnostic Procedures/Other
  • Lymph node biopsy
  • Brain biopsy in CNS disease
  • Amniocentesis with PCR (risk of false negatives and false positives)
  • Placental isolation of Toxoplasma is diagnostic.
Test Interpretation
  • Confirmatory, meningocerebritis ± abscesses with necrosis, Giemsa
  • Lymph node histology shows triad of:
    • Reactive follicular hyperplasia
    • Irregular clusters of epithelioid histiocytes on and blurring margins of germinal centers
    • Distension of sinuses with monocytoid cells
  • Sensitivity of triad 62.5%, specificity 91.3%
image TREATMENT
GENERAL MEASURES
Immunocompetent patients usually require no treatment.
MEDICATION
First Line
  • Treatment in immunocompromised hosts
    • Initial regimen of choice is pyrimethamine 200 mg loading dose PO, followed by 50 mg/day plus sulfadiazine 4 to 6 g/day PO in 4 divided doses; for those intolerant or allergic to sulfadiazine, clindamycin 600 to 1,200 mg IV or 450 mg PO QID can be used instead.
    • Alternative regimens for patients intolerant to sulfadiazine and clindamycin include the following:
      • Pyrimethamine: 200 mg loading dose PO, followed by 50 mg/day plus azithromycin 900 to 1,200 mg PO once daily
      • Pyrimethamine: 200 mg loading dose PO, then 50 mg/day plus atovaquone 1,500 mg PO BID
      • Sulfadiazine: 1,000 to 1,500 mg QID plus atovaquone 1,500 mg BID
      • Trimethoprim-sulfamethoxazole: 10/50 mg/kg/day PO or IV divided BID (for 30 days) may be a costeffective alternative.
    • Duration of therapy: typically 6 weeks, lower doses for secondary prophylaxis (2)[A]
    • Use adjunctive steroids should in patients with signs of increased intracranial pressure.
    • Anticonvulsants, if there is a history of seizures
  • Prophylaxis in immunocompromised patients
    • Primary prophylaxis: indicated for patients with HIV infection and CD4 count <100 cells/&mgr;L who are T. gondii IgG-positive
      • Trimethoprim-sulfamethoxazole-DS: 1 tablet PO daily. Alternative for sulfa allergy is dapsone 50 mg/day PO plus pyrimethamine 50 mg PO weekly plus leucovorin 25 mg PO weekly or atovaquone 1,500 mg PO daily.
    • Secondary prophylaxis: Following 6 weeks of therapy, administer lower doses of drugs:
      • Sulfadiazine 2 to 4 g/day in two to four divided doses plus pyrimethamine 25 to 50 mg/day is the first choice.
      • Alternative regimens include clindamycin 600 mg PO q8h plus pyrimethamine 25 to 50 mg/day PO or atovaquone 750 mg PO BID to QID ± pyrimethamine 25 mg PO daily.
  • Pregnant women (3)[A]
    • There is a lack of evidence on whether antenatal treatment reduces congenital transmission; however, prenatal treatment is usually offered.
    • <18 weeks' gestation: Spiramycin 1 g PO q8h without food until delivery if amniotic fluid PCR is negative. Does not treat infection in the fetus
    • >18 weeks' gestation: Pyrimethamine and sulfadiazine should be considered only if fetal infection is documented by positive amniotic fluid PCR (pyrimethamine is teratogenic):
      • Pyrimethamine: 50 mg PO q12h for 2 days, then 50 mg/day plus sulfadiazine 75 mg/kg PO ˜ 1 dose, then 50 mg/kg q12h (max 4 g/day)
  • Treat infected newborns regardless of clinical manifestations:
    • Pyrimethamine 2 mg/kg/day (max 50 mg) for 2 days; then 1 mg/kg/day (max 25 mg) for 2 to 6 month; then 1 mg/kg (max 25 mg) on Monday, Wednesday, and Friday; sulfadiazine 100 mg/kg/day divided BID; and leucovorin 10 mg three times per week during pyrimethamine and 1 week after discontinuation
  • Immunocompetent nonpregnant patients generally do not require treatment unless symptoms are severe or prolonged; 1 of 2 regimens can be used:
    • Pyrimethamine: 100 mg loading dose PO, followed by 25 to 50 mg/day plus sulfadiazine 2 to 4 g/day in four divided doses
    • Pyrimethamine: 100 mg loading dose PO, followed by 25 to 50 mg/day plus clindamycin 300 mg PO QID
Second Line
  • Clindamycin: 900 to 1,200 mg TID IV used for ocular and CNS toxoplasmosis alone and in combination with pyrimethamine; as effective as the sulfadiazine-pyrimethamine with fewer adverse effects
  • Corticosteroids (prednisone 1 to 2 mg/kg/day) are added for macular chorioretinitis or CNS infection.
  • Alternatives: atovaquone (Mepron), azithromycin (Zithromax), clarithromycin (Biaxin), or dapsone plus pyrimethamine and leucovorin
  • Trimethoprim-sulfamethoxazole appears to be equivalent to pyrimethamine-sulfadiazine in AIDS patients with CNS disease.
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
Precautions
  • Monitor for bone marrow, renal, or liver toxicity.
  • Good hydration: Sulfadiazine is poorly soluble and may crystallize in the urine.
  • Watch for antibiotic-associated diarrhea.
  • Sulfonamides may alter phenytoin and warfarin levels or interfere with oral hypoglycemic agents.
PATIENT EDUCATION
  • http://www.aafp.org/afp/2003/0515/p2145.html
  • http://familydoctor.org/familydoctor/en/diseases-conditions/toxoplasmosis.html
PROGNOSIS
  • Immunodeficient patients often relapse if treatment or suppression therapy is stopped.
  • Treatment may prevent the development of untoward sequelae in infants with congenital toxoplasmosis.
REFERENCES
1. Torgerson PR, Mastroiacovo P. The global burden of congenital toxoplasmosis: a systematic review. Bull World Health Organ. 2013;91(7):501-508.
2. Montoya JG, Liesenfeld O. Toxoplasmosis. Lancet. 2004;363(9425):1965-1976.
3. Montoya JG, Remington JS. Management of Toxoplasma gondii infection during pregnancy. Clin Infect Dis. 2008;47(4):554-566.
Additional Reading
&NA;
  • Arantes TE, Silveira C, Holland GN, et al. Ocular involvement following postnatally acquired Toxoplasma gondii infection in Southern Brazil: a 28-year experience. Am J Ophthalmol. 2015; 159(6):1002.e2-1012.e2.
  • Bodaghi B, Touitou V, Fardeau C, et al. Toxoplasmosis: new challenges for an old disease. Eye (Lond). 2012; 26(2):241-244.
  • Garweg JG, Stanford MR. Therapy for ocular toxoplasmosis—the future. Ocul Immunol Inflamm. 2013;21(4):300-305.
  • Kaplan JE, Benson C, Holmes KH, et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep. 2009;58(RR-4):1-207.
  • Wallon M, Franck J, Thulliez P, et al. Accuracy of real-time polymerase chain reaction for Toxoplasma gondii in amniotic fluid. Obstet Gynecol. 2010;115(4):727-733.
Codes
&NA;
ICD10
  • B58.9 Toxoplasmosis, unspecified
  • P37.1 Congenital toxoplasmosis
  • B58.2 Toxoplasma meningoencephalitis
Clinical Pearls
&NA;
  • Toxoplasmosis is often asymptomatic in immunocompetent patients, who often don't need treatment for clinical disease.
  • Primary prevention is important, particularly for pregnant women and immunodeficient patients.
  • The most common manifestation of acute toxoplasmosis in immunocompetent host is bilateral, symmetric, nontender cervical lymphadenopathy.
  • Universal screening for congenital toxoplasmosis is not currently recommended.