MICROBIOLOGY

  • Protozoan parasite, oocysts shed by cats (definitive hosts).
  • Oocysts sporulate and become infectious after 1-5 days, are resistant to freezing, and survive > 1 yr in moist environments, e.g., soil. Oocysts transform into tachyzoites, localize in muscle and neural tissue, then develop into tissue bradyzoites.
  • Transmitted by:
    • Ingestion of sporulated oocysts via contamination of litter box, sandbox or garden as well as drinking water, fruits and vegetables, or raw seafood. [9]
    • Consumption of raw or undercooked meat containing tissue cysts, esp. pork, lamb, and wild game meat. Free-range animals may have greater risk of contamination. [9]
    • In utero, if primary maternal infection during or just prior to pregnancy.
    • Organ transplant or blood transfusion from seropositive donor to seronegative recipient.
    • Note: risks factors are commonly unrecognized by those infected. [13]
  • Seroprevalence varies by region, high prevalence rates in Latin America, parts of Eastern/Central Europe, the Middle East, parts of south-east Asia and Africa. [15]

CLINICAL

  • Primary infection:
    • In the immunocompetent host, usually self-limited disease.
      • May be asymptomatic or mild illness with fever, malaise, and painless lymphadenitis (single and cervical, multiple or generalized).
      • Constitutional symptoms, e.g., fatigue, may take weeks or months to resolve.
      • Occasionally, primary infection may be associated with acute cerebral or disseminated disease. [12]
    • Solid organ transplant recipients: most often seen in first month after transplant (heart >> liver, kidney).
  • Secondary infection: reactivation of latent infection in those immunosuppressed due to AIDS, cancer therapy, transplantation or iatrogenic therapies.
    • Toxoplasma encephalitis (TE): presents as fever, headache, confusion, seizure, focal motor findings with ring-enhancing lesions in setting of AIDS (CD4 < 50). May present as non-focal, non-specific illness with headache and psychiatric symptoms. [6]
    • Pulmonary toxoplasmosis: often life-threatening infection in highly immunosuppressed, i.e., allogeneic HSCT.
      • Prophylaxis routine in those who are seropositive.
  • Ocular disease: in infants, children, or adults with congenital retinochoroiditis; during pregnancy; and in acute or reactivated infection in immunocompromised host.
    • Most common cause of posterior uveitis. dx by ophthalmologic exam.
      • Retinochoroiditis, intensely white lesions in clusters, with vitreous inflammation, satellite lesions, retinochoroidal scar, retina vasculitis, and granulomatous anterior chamber inflammation in a third of patients. [2] May cause visual field loss if located near the optic disc.
      • Differential dx: CMV, HSV, VZV, syphilis, fungal infections.
    • Self-limited disease in immunocompetent; lesions in acute infection most often unilateral and spare the macula. Those with late sequelae of congential infection have bilateral disease, retinal scars and macular involvement.
    • Active retinochoroiditis, esp. in immunocompromised host, may present as reduced visual acuity due to intense vitritis, macular traction, or detachment. Treatment aim to control damage to retina and optic disc and decrease tachyzoite load. [3]
  • Congenital disease: transplacental infection of fetus if mother acutely infected during pregnancy.
    • Incidence and severity depends on gestational age at time of maternal infection.
      • Early pregnancy congenital infection rare
      • Fetal outcomes are severe: miscarriage, stillbirth or severe CNS sequelae.
    • Transmission risk inconsistent throughout pregnancy. Primary maternal infection in latter half of pregnancy more frequently associated with congenital infection, most infected infants born healthy, 22% with clinical disease at 3 yrs. [11]
  • Dx (acute)
    • Serology: seroconversion or 4-fold rising titers necessary to confirm new infection.
      • Cannot reliably diagnose acute infection with single IgM, as test can remain positive for ≥2 yrs.
    • Histopathology: may demonstrate organisms in tissue biopsies from afflicted organs.
    • Special Population--pregnancy, immunocompetent:
      • Serology: toxoplasma IgG positive, IgM negative in first or second trimester is high likelihood that maternal infection is remote and without risk to fetus.
        • Positive IgM +/- IgG should prompt further testing using reference lab, e.g., Palo Alto Medical Foundation Toxoplasma Reference Laboratory (PAMFRL) [7] or National Collaborative Chicago-based Congenital Toxoplasmosis Study (NCCCTS) [13], to run toxo panels: Sabin-Feldman dye test, IgA and IgE ELISA, differential agglutination and IgG avidity tests.
      • Ultrasound, fetal: may detect ventriculomegaly, intracranial calcifications or hepatosplenomegaly.
      • Amniocentesis: test fluid using T. gondii PCR.
        • Perform at ≥ 18 wks gestational age and ≥ 4 wks after presumed acquisition of infection to reduce risk of false negative.
        • Negative predictive value (98.8%).
  • Dx (reactivation): empiric diagnosis for CNS lesions based on serology and typical imaging.
    • Serology: almost all HIV patients with CNS lesions are seropositive by IgG; if seronegative, toxo much less likely.
    • Imaging: for TE, contrast-enhanced CT or MRI shows multiple ring-enhancing lesions with surrounding edema in gray matter of cortex or basal ganglia.
      • Occasionally TE can present as a single lesion.
      • PET or SPECT scans may help distinguish between toxo and primary CNS lymphoma, but are not reliably specific.
      • Lack of radiologic response after 2 wks of anti-toxo therapy is an indication to consider alternative diagnosis.
    • Histopathology: direct detection of parasite by microscopy.
      • Stereotactic CT-guided brain biopsy usually reserved for patients unresponsive to 2 wks of therapy.
    • Culture: blood or tissue, especially in immunocompromised pts (rarely done, difficult and expensive).
    • PCR: CSF for T. gondii, high specificity (96%--100%), low sensitivity (50%). [6]

SITES OF INFECTION

  • CNS: encephalitis, seizures, coma.
    • Multifocal lesions on contrast-enhanced brain CT or MRI, esp. of basal ganglia.
    • Typical radiographic appearance + therapeutic response = presumed diagnosis.
  • Ocular: posterior uveitis, retinochoroiditis, unilateral, unifocal, large lesion; can be necrotizing, important to distinguish from CMV or VZV (PORN) in AIDS.
  • Lymph node: isolated, multiple or generalized lymphadenopathy.
  • Heart: myocarditis, in the severely immunocompromised.
  • Lung: pneumonitis, in HSCT recipients.
  • Cutaneous: rare, may appear like erythema multiforme, nodules, urticaria or maculopapular lesions. Diagnose by skin biopsy displaying tachyzoites.
  • Systemic: dissemination seen in congenital infection and reported in Amazonia toxoplasmosis. [12]

TREATMENT

Primary Infection

  • Acute, self-limited disease in immunocompetent, non-pregnant patient usually requires no treatment.
  • Treatment if visceral disease or symptoms are severe or persistent (see below).

Immunocompromised/reactivation Infection

  • TE often treated empirically, evidence of clinical and radiographic response to 2 wks of therapy is considered supportive of diagnosis.
  • Preferred: treatment duration, 6 wks: [6]
    • Duration: for initial therapy, >6 wks may be required, if slow or incomplete response.
    • Leucovorin (folinic acid) 10-25 mg PO daily, reverses bone marrow suppression of pyrimethamine.
  • Alternatives:
  • If pt unable to take PO: little data exist regarding parenteral options.
  • If corticosteroids needed for CNS mass effect, use shortest duration possible.
  • Anticonvulsants as prophylaxis are not recommended.

Secondary Prophylaxis (TE in AIDS)

  • Preferred: chronic maintenance
    • Pyrimethamine 25-50 mg PO daily + sulfadiazine 2000-4000 mg PO in 2-4 divided doses + leucovorin 10-25 mg PO daily.
    • Discontinue once asymptomatic and CD4 >200 for >6 mos. [6]
  • Alternatives:

Pregnancy

  • Maternal treatment of primary toxoplasmosis or acute infection is same as in non-pregnant adults.
    • HIV: primary prophylaxis for TE with TMP/SMX also involves potential for birth defect (cardiovascular) risk of TMP/SMX during 1st trimester.
  • Prevention of vertical transmission:
    • Early pregnancy/1st trimester, if mother found to seroconvert
      • Spiramycin 1g every 8hr, does not cross placenta, not used for fetal treatment.
    • Beyond 1st trimester (≥ 18wks) or confirmed fetal infection (e.g., by PCR):
      • Pyrimethamine 50 mg twice daily x 2d then 50 mg per day + sulfadiazine 75 mg/kg/d in two divided doses x 2d then 50 mg/kg twice daily + leucovorin 10-20 mg daily.
      • May reduce risk of congenital toxoplasmosis development or treat fetal infection.
      • Due to teratogenicity concerns, pyrimethamine should not be used in the first trimester.
  • Prevention of acquiring infection/maternal:
    • Educate expectant mothers to avoid changing cat litter, avoid raw or undercooked meats.
    • Some countries and states check monthly serology during pregnancy.

Primary Prophylaxis

  • HIV/AIDS, Preferred: for T. gondii IgG+ patients with CD4 < 100
  • Alternatives:
  • Discontinue prophylaxis for CD4 >200 for >3 mos.
  • Solid organ transplant:TMP/SMX post-transplant prophylaxis recommended in seronegative recipient, seropositive donor.
  • HSCT patients: prophylaxis with TMP/SMX in those seropositive, consider hematologic toxicity.
    • Alt: pyrimethamine-sulfadiazine

Ocular Toxo

  • Oral systemic ’classic’ therapy: use sulfadiazine, pyrimethamine, leucovorin and systemic corticosteroids
    • Limited by adverse drug reactions (reversible pancytopenia, GI intolerance, neurologic effects)
    • No role for steroids as sole therapy, must be accompanied by antiparasitic agents.
  • Intravitreous injection: clindamycin and dexamethasone [14]
    • Localized treatment to site of infection with reduced systemic complications and high concentration in intraocular tissue
    • No difference in efficacy reported in RCT comparing oral and intravitreal injections (n=68) with 1.6 mean number of injections: 18 (53%), 1 injection; 11 (32%), 2 injections; and 5 (15%), 3 injections. Subconjunctival hemorrhage in 3 (9%), transient raised intraocular pressure in 1 (3%). No occurrences of virteous hemorrhage, endophthalmitis, retinal detachment or cataract reported. [4]
  • In development, intraocular biodegradable polymer implants for controlled-release of clindamycin [8]
  • Secondary prophylaxis
    • TMP/SMX preferred
    • RCT (n=95) for 12 mos follow-up, reported zero recurrences in treatment arm versus 13% recurrences in placebo arm. [1]

Selected Drug Comments

Drug

Recommendation

Azithromycin

Alternate therapy for TE, may replace sulfadiazine in combination with pyrimethamine.

Clindamycin

Alternate therapy for TE, may replace sulfadiazine in combination with pyrimethamine.

Dapsone

Alternate therapy for TE, may replace sulfadiazine in combination with pyrimethamine.

Trimethoprim/sulfamethoxazole

Preferred therapy for primary TE and PCP prophylaxis. Adverse reactions include rash, cytopenias, LFT abnormalities and hyperkalemia.

Atovaquone

Alternate therapy for TE, may replace sulfadiazine in combination with pyrimethamine.

Pyrimethamine/sulfadiazine

Preferred therapy for TE. Leucovorin serves as rescue to reverse pyrimethamine-associated adverse effects: bone marrow suppression, nausea, and rash.

Spiramycin

Drug of choice for maternal treatment of newly infected women in early pregnancy to prevent vertical transmission.

Basis for recommendation

  1. Felix JP et al: Trimethoprim-sulfamethoxazole versus placebo to reduce the risk of recurrences of Toxoplasma gondii retinochoroiditis: randomized controlled clinical trial. Am J Ophthalmol 157:762, 2014  [PMID:24388839]

    Comment: Single center Brazilian RCT (n=95) evaluated secondary prevention of Toxoplasma gondii retinochoroiditis with TMP_SMX for 12 mos follow-up, reported zero (0/46) recurrences in treatment arm versus 13% (6/47) recurrences in placebo arm.

  2. Harrell M, Carvounis PE: Current treatment of toxoplasma retinochoroiditis: an evidence-based review. J Ophthalmol 2014:, 2014  [PMID:25197557]

    Comment: Review of ocular toxoplasmosis treatment finds TMP-SMX is preferred first-line therapy with intravitreous clindamycin plus dexamethasone as an alternative in those who are unresponsive or cannot tolerate oral tx or during pregnancy, TMP-SMX is effective secondary preventive therapy, and corticosteroids without antiparasitics should be avoided as this can lead to fulminant necrotizing retinochoroiditis.

  3. Montoya JG, Remington JS: Management of Toxoplasma gondii infection during pregnancy. Clin Infect Dis 47:554, 2008  [PMID:18624630]

    Comment: Serological screening remains the main tool for prevention of congenital toxoplasmosis along with educating mothers to be about potential risk factors. This paper reviews many of the complex diagnostic and treatment decisions of this infection during pregnancy.

  4. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents. Department of Health and Human Services. Available at: http://aidsinfo.nih.gov…. Accessed 3/23/15.

    Comment: In era before ART, 33% of those seropositive for T. gondii w/AIDS not on OI prophylaxis developed toxoplasmic encephalitis in 12 month period. Immune reconsistution on ART, chemoprophylaxis if CD4 < 100, and exposure prevention are priorities. TMP-SMX DS 1 tab po qd is preferred, recommended alternative is dapsone-pyrimethamine plus leucovorin. Discontinuation of primary prophylaxis in those with CD4 >200 for >3mos.

  5. Soheilian M et al: Randomized trial of intravitreal clindamycin and dexamethasone versus pyrimethamine, sulfadiazine, and prednisolone in treatment of ocular toxoplasmosis. Ophthalmology 118:134, 2011  [PMID:20708269]

    Comment: RCT of 68 pts with ocular toxoplasmosis were treated with oral therapy (pyrimethamine, sulfadiazine, and prednisolone x 6 wks) or clindamycin plus dexamethasone intravitreal injections (1-3 injections, mean 1.6 injections) found no difference in lesion size reduction and visual acuity improvement. Interaction of IgM serostatus and lesion size reduction was significant; IgM+ pts responded better to oral therapy and IgM- pts responded better to intravitreal injections.

  6. de-la-Torre A et al: Therapy for ocular toxoplasmosis. Ocul Immunol Inflamm 19:314, 2011  [PMID:21970662]

    Comment: Expert recommendation for ocular toxoplasmosis by clinical scenerio: infants with congenital infection, woman who are pregnant, and adult active retinochoroiditis. Regimens include: classic therapy- oral pyrimethamine, sulfadiazine, folinic acid plus corticosteroids; oral TMP-SMX plus corticosteroids; and intravitreal injection of clindamycin and dexamethasone.

References

  1. Boyer K et al: Unrecognized ingestion of Toxoplasma gondii oocysts leads to congenital toxoplasmosis and causes epidemics in North America. Clin Infect Dis 53:1081, 2011  [PMID:22021924]

    Comment: Cross-sectional study correlated serum antibody to 11-kDa sporozoite protein in 59 of 76 (78%) acutely infected mothers who transmitted T. gondii to their fetuses in utero to known risk factors, i.e., exposure to cats, oocyst-contaminated soil, and meat not cooked to well-done. Detection of anti-sporozoite antibodies identified oocysts as infection source rather than bradyzoites in tissue cysts. Transmission risks were identified in 49%, suggesting that undetected contamination of food and water by oocysts may be frequent and unrecognized source of infection. Furthermore, US does not employ gestational serologic screening program, which given the lack of reliable risk factors, would have the greatest likelihood of preventing fetal disease.
    Rating: Important

  2. Demar M et al: Acute toxoplasmoses in immunocompetent patients hospitalized in an intensive care unit in French Guiana. Clin Microbiol Infect 18:E221, 2012  [PMID:21958195]

    Comment: Characterization of ’Amazonian toxoplasmosis’ manifest as acute, disseminated toxoplasmosis with pneumonia in French Guiana included 11 patients (9 men, 8 permanent forest-dwellers, 8 with dietary risk factors, i.e., ingestion of raw game meat, carpaccio) treated with sulfadiazine and pyrimethamine, 2 switched from sulfadiazine to clindamycin. Authors suggest that T. gondii strains found in Amazon basin are more aggressive and result in severe pulmonary disesase more often than strains isolated in Europe and North America.
    Rating: Important

  3. Jones JL et al: Ocular toxoplasmosis in the United States: recent and remote infections. Clin Infect Dis 60:271, 2015  [PMID:25301214]

    Comment: Survey of T. gondii Ab+ serum samples from 205 patients diagnosed with ocular toxoplamosis from 2004 to 2010 confirmed by Palo Alto Medical Foundation Toxoplasma Reference Laboratory, employed acute serologic profile and detected recent infection (within 6 mos) in 24 patients (12%). Authors conclude that ocular disease may develop soon after acquiring T. gondii infection in a larger percent of the population (>10%) than previously believed.
    Rating: Important

  4. Lasave AF et al: Intravitreal clindamycin and dexamethasone for zone 1 toxoplasmic retinochoroiditis at twenty-four months. Ophthalmology 117:1831, 2010  [PMID:20471684]

    Comment: Case series (n=12) of intravitreal clindamycin and dexamethasone in 4 pts (3 pregnant, 1 intolerant of oral tx) and oral therapy in 8 pts (6 pts, TMP-SMX and clindamycin; 2 pts, pyrimethamine, sulfadiazine, folinic acid). Mean number of injections of 3.6 (range: 2-5 injections) with a mean interval of 15.5+/-4 days. Ten eyes improved and 2 eyes remained stable at 24 mos. One report of macular scarring.

  5. Matias M et al: Ocular toxoplasmosis: a very rare presentation in an immunocompetent patient. BMJ Case Rep 2014:, 2014  [PMID:25270156]

    Comment: Case report of immunocompetent, Brazilian man with right unilateral eye pain, redness, photophobia and decreased visual acuity accompanied by retinochoroiditis. Initial treatment included azithromycin, pyrimethamine, and topical steroids. After 1 wk of therapy, patient presented with HA, vomiting and decreased right eye visual acuity. CT, MRI, and LP did not reveal evidence of cerebral toxoplasmosis. Interim therapy included pyrimethamine, sulfadiazine, prednisolone, and folic acid. Secondary prevention included TMP-SMX. Southern Brazil reports high prevalence of ocular toxoplasmosis.

  6. Opsteegh MM et al: Intervention strategies to reduce human Toxoplasma gondii disease burden. Clin Infect Dis Sep 15  [PMID:25225234]

    Comment: Public health interventions to reduce T. gondii burden of disease include: prenatal and neonatal screening and treatment, health education of pregnant women and general population, biosecurity programs with exposure reduction, vaccination of food animals, and decontamination of meat. Other considerations include reducing stray cat population, educating cat owners, and vaccinating cats.

  7. Pappas G, Roussos N, Falagas ME: Toxoplasmosis snapshots: global status of Toxoplasma gondii seroprevalence and implications for pregnancy and congenital toxoplasmosis. Int J Parasitol 39:1385, 2009  [PMID:19433092]

    Comment: Global seroprevalence of T. gondii in women of child-bearing age and during pregnancy based on published reports including at least 100 indivuduals of general population, excluded at-risk populations, i.e., HIV+, immunocompromised, and slaughterhouse workers. Highest rates (>60%) in Brazil and Madagascar, 40-60% seroprevalence in Cuba, Columbia, southern Mexico. Authors note that high seroprevalence may translate to protection from primary infection during pregnancy, and conversely, in areas of low prevalence, an increased risk of primary infection, abortion, and congenital toxoplasmosis.
    Rating: Important

  8. Tamaddon L et al: Design and development of intraocular polymeric implant systems for long-term controlled-release of clindamycin phosphate for toxoplasmic retinochoroiditis. Adv Biomed Res 4:, 2015  [PMID:25709997]

    Comment: In vitro drug release kinetics described for intracular biodegradable polymer implant suggest that in vivo long-term controlled release of clindamycin could be used to treat retinochoroiditis and avoid adverse effects of oral therapy and repeated intravitral injections.
    Rating: Important

  9. Wallon M et al: Congenital toxoplasma infection: monthly prenatal screening decreases transmission rate and improves clinical outcome at age 3 years. Clin Infect Dis 56:1223, 2013  [PMID:23362291]

    Comment: Observational cohort of 2048 pregnant women diagnosed with acute Toxoplasma infections at reference lab in Lyon, France. The majority (93%) received treatment. Risk of congential infection varied with gestational age: < 10% before 12 wks, 20% at 19 wks, 52% at 28 wks, and 70% at 39 wks. The majority of infected infants were healthy, 22% had clinical signs at age 3 yrs. Authors recommend fetal monitoring and amniocentesis with PCR of fluid to prevent unnecessary antenatal treatment.
    Rating: Important

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Last updated: May 13, 2015