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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/ ΌL
- 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.
DIAGNOSIS
HISTORY
- Congenital toxoplasmosis
- Clinical presentation varies widely; 80% of patients are asymptomatic at birth.
- Classic triad (uncommon): chorioretinitis, hydrocephalus, cerebral calcifications
- Manifestations may include prematurity, intrauterine growth retardation (IUGR).
- Jaundice, rash accompanying a mononucleosis-like illness
- Mental retardation, seizures, visual defects, spasticity, sensorineural hearing loss
- Ocular toxoplasmosis
- Chorioretinitis: focal necrotizing retinitis
- Yellowish-white elevated cotton patch
- Congenital disease usually bilateral; acquired is more often unilateral.
- Symptoms include blurred vision, scotoma, pain, and photophobia.
- Acute toxoplasmosis (immunocompetent host)
- ’ Ό90% of patients are asymptomatic.
- Most common manifestation is bilateral, symmetric, nontender cervical lymphadenopathy.
- Constitutional symptoms such as fever, chills, and sweats are usually mild.
- Headaches, myalgias, pharyngitis, hepatosplenomegaly, and diffuse nonpruritic maculopapular rash may occur.
- Pregnant women are often asymptomatic.
- Most common site is CNS with toxoplasmic encephalitis.
- Headache; focal neurologic deficits and seizures
- Fever usually present
- Extracerebral toxoplasmosis: pneumonitis; chorioretinitis; rarely: GI system, liver, musculoskeletal system, heart, bone marrow, bladder, and orchitis
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.
- 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%
TREATMENT
GENERAL MEASURES
Immunocompetent patients usually require no treatment.
MEDICATION
First Line
ALERT
Important: All pyrimethamine-containing regimens should include leucovorin (folinic acid 10 to 25 mg/day PO) during and 1 week after completion of pyrimethamine to prevent drug-induced hematologic toxicity (2)[A].
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 four 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 cost-effective 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/ ΌL who are T. gondii IgG " positive
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):
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.
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
11 Torgerson PR, Mastroiacovo P. The global burden of congenital toxoplasmosis: a systematic review. Bull World Health Organ. 2013;91(7):501 " 508.22 Montoya JG, Liesenfeld O. Toxoplasmosis. Lancet. 2004;363(9425):1965 " 1976.33 Montoya JG, Remington JS. Management of Toxoplasma gondii infection during pregnancy. Clin Infect Dis. 2008;47(4):554 " 566.
ADDITIONAL READING
- 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
ICD10
- B58.9 Toxoplasmosis, unspecified
- P37.1 Congenital toxoplasmosis
- B58.2 Toxoplasma meningoencephalitis
- B58.00 Toxoplasma oculopathy, unspecified
ICD9
- 130.9 Toxoplasmosis, unspecified
- 771.2 Other congenital infections specific to the perinatal period
- 130.0 Meningoencephalitis due to toxoplasmosis
- 130.7 Toxoplasmosis of other specified sites
SNOMED
- 187192000 Toxoplasmosis (disorder)
- 73893000 Congenital toxoplasmosis (disorder)
- 192701001 Toxoplasma encephalitis (disorder)
- 416481006 Ocular toxoplasmosis
- 16116004 Acute lymphadenopathic toxoplasmosis
CLINICAL PEARLS
- 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.