MICROBIOLOGY

  • Protozoan parasite causes worldwide zoonosis, prevalent in humans and food animals. Cats shed oocysts, which are resistant to freezing and survive > 1 yr in moist environments, e.g., soil. Humans are an intermediate host.
  • Oocysts sporulate and become infectious after 1-5 days. Oocysts transform into tachyzoites, localize in muscle and neural tissue, then develop into tissue bradyzoites.[7]
  • 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.[11]
    • Consumption of raw or undercooked meat containing tissue cysts, esp. pork, lamb, and wild game meat[15]. Free-range animals have a greater risk of contamination.
    • In utero, if primary maternal infection occurs during or just prior to pregnancy.[17]
    • Organ transplant or blood transfusion from seropositive donor to seronegative recipient.
  • 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.[19]

CLINICAL

  • Primary infection:
    • In the immunocompetent host, the disease is usually self-limited.
      • Maybe 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, the primary infection may be associated with acute cerebral or disseminated disease.[16]
    • Solid organ transplant recipients: most often seen in the first month after transplant in the seronegative recipient (R-) from a donor (D+) organ (R-/D+), the risk is highest for heart transplants (heart >> liver, kidney).[10]
  • Secondary infection: reactivation of latent infection in those immunosuppressed due to AIDS, cancer therapy, transplantation or biologic therapies.
    • Toxoplasma encephalitis (TE): presents as fever, headache, confusion, seizure, focal motor findings with ring-enhancing lesions. May present as a non-focal, non-specific illness with headache and psychiatric symptoms.[6]
      • Hematopoietic stem cell transplants (HSCT) recipients, the risk is highest for seropositive allo-HSCT recipient receiving a seronegative graft.[10]
      • HIV/AIDS with CD4 < 50 at greatest risk.[6]
    • Pulmonary toxoplasmosis: often life-threatening infection in highly immunosuppressed, i.e., allo-HSCT.
      • Prophylaxis routine in those who are seropositive allo-HSCT recipient.
  • Ocular disease: in infants, children, or adults with congenital retinochoroiditis; during pregnancy; and in acute or reactivated infection in an immunocompromised host.
    • The most common cause of posterior uveitis. Dx by ophthalmologic exam, ocular fluid PCR.
      • 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 congenital infection have bilateral disease, retinal scars and macular involvement.
    • Active retinochoroiditis, especially in an immunocompromised host, may present as reduced visual acuity due to intense vitritis, macular traction, or detachment. Treatment aims to control damage to the retina and optic disc and decrease tachyzoite load.[3]
  • Congenital disease: transplacental infection of the fetus, if mother acutely infected during pregnancy.
    • Incidence and severity depend on gestational age at the time of maternal infection. Transmission risk inconsistent throughout pregnancy.
      • Early pregnancy congenital infection rare
    • Primary maternal infection in the latter half of pregnancy more frequently associated with congenital infection, most infected infants born healthy, 22% with clinical disease at 3 yrs.[14]
      • Fetal outcomes are severe: miscarriage, stillbirth or severe CNS sequelae.
  • Dx (acute)
    • Serology: seroconversion or 4-fold rising titers necessary to confirm new infection.
      • Cannot reliably diagnose acute infection with single IgM, as the test can remain positive for ≥2 yrs.
    • Histopathology: may demonstrate organisms in tissue biopsies from infected organs.
    • Special Population--pregnancy, immunocompetent:
      • Serology: toxoplasma IgG positive, IgM negative in the first or second trimester is a high likelihood that maternal infection is remote and without risk to the fetus.
        • Positive IgM +/- IgG should prompt further testing using reference lab, e.g., Palo Alto Medical Foundation Toxoplasma Reference Laboratory (PAMFRL)[12] or National Collaborative Chicago-based Congenital Toxoplasmosis Study (NCCCTS)[17], to run toxoplasma 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 the presumed acquisition of infection to reduce risk of a 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, toxoplasma much less likely.
    • Imaging: for TE, contrast-enhanced CT or MRI shows multiple ring-enhancing lesions with surrounding edema in the 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 an alternative diagnosis.
    • Histopathology: direct detection of the 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] Ocular fluid, small volume aqueous tap, 0.1mL for multiplex PCR.[9]

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 is seen in congenital infection, R-/D+ organ transplant,[7] and reported in Amazonia toxoplasmosis.[16]

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

Secondary Prophylaxis (TE in AIDS)

Pregnancy

  • Maternal treatment of primary toxoplasmosis or acute infection is the same as in non-pregnant adults.
    • HIV: primary prophylaxis for TE with TMP/SMX also involves the potential for birth defect (cardiovascular) risk of TMP/SMX during first trimester.
  • Prevention of vertical transmission:
    • Early pregnancy/first trimester, if mother found to seroconvert
      • Spiramycin 1g every 8hr, does not cross the 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 the risk of congenital toxoplasmosis development or treat the 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 a sole therapy, must be accompanied by antiparasitic agents.
  • Intravitreous injection: clindamycin and dexamethasone[18]
    • Localized treatment to the 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 vitreous hemorrhage, endophthalmitis, retinal detachment or cataract reported.[4]
  • In development, intraocular biodegradable polymer implants for controlled-release of clindamycin[13]
  • Secondary prophylaxis
    • TMP/SMX preferred
    • RCT (n=95) for 12 mos follow-up, reported zero recurrences in the treatment arm versus 13% recurrences in the 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 a 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, Lira RP, Zacchia RS, et al. Trimethoprim-sulfamethoxazole versus placebo to reduce the risk of recurrences of Toxoplasma gondii retinochoroiditis: randomized controlled clinical trial. Am J Ophthalmol. 2014;157(4):762-766.e1.  [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 the treatment arm versus 13% (6/47) recurrences in the placebo arm.

  2. Harrell M, Carvounis PE. Current treatment of toxoplasma retinochoroiditis: an evidence-based review. J Ophthalmol. 2014;2014:273506.  [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. de-la-Torre A, Stanford M, Curi A, et al. Therapy for ocular toxoplasmosis. Ocul Immunol Inflamm. 2011;19(5):314-20.  [PMID:21970662]

    Comment: Expert recommendation for ocular toxoplasmosis by clinical scenario: infants with congenital infection, a 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.

  4. Soheilian M, Ramezani A, Azimzadeh A, et al. Randomized trial of intravitreal clindamycin and dexamethasone versus pyrimethamine, sulfadiazine, and prednisolone in treatment of ocular toxoplasmosis. Ophthalmology. 2011;118(1):134-41.  [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.

  5. Montoya JG, Remington JS. Management of Toxoplasma gondii infection during pregnancy. Clin Infect Dis. 2008;47(4):554-66.  [PMID:18624630]

    Comment: Serological screening remains the main tool for the 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.

  6. 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: https://aidsinfo.nih.gov/guidelines/html/4/adult-and-adolescent-opportunistic-infection/322/toxoplasma-gondii. Accessed 7/26/19.

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

References

  1. Lee Loy J, Koratala A, De Los Santos Y, et al. Disseminated toxoplasmosis: a life-threatening complication of inadequate posttransplant prophylaxis. Kidney Int. 2019;95(5):1274.  [PMID:31010482]

    Comment: Case report of disseminated toxoplasmosis in cadaveric kidney (R-/D+) transplant where TMP/SMX was avoided due to hyperkalemia and OI prophylaxis with aerosolized pentamidine targeting Pneumocystis jirovecii did not prevent toxoplasmosis. The patient received alemtuzumab for induction followed by mycophenolate mofetil, tacrolimus, and prednisone for maintenance immunosuppression. One month post-transplant, the patient presented with fever, hypotension and progressed to acute respiratory distress and death within 2 days. Post-mortem testing was positive for T gondii by serology and histology (heart and lung biopsies).

  2. Galván-Ramírez ML, Sánchez-Orozco LV, Andrade-Sierra J, et al. Toxoplasma infection in kidney donors and transplant recipients from Western Mexico: A one-year follow-up. Transpl Infect Dis. 2019.  [PMID:31271696]

    Comment: In renal transplant donors (N=99) and recipients (N=99) in Western Mexico followed for 12 months from 2014-2016, baseline frequency of IgG seropositivity was greater in donors (38%) than recipients (25%). Seroconversion was seen in 3% and reactivation was seen in 11%. All recipients receive prophylaxis with TMP/SMX for 3 months after transplant. Neither T. gondii DNA nor clinical cases of toxoplasmosis were observed.

  3. Minkus CL, Bispo PJM, Papaliodis GN, et al. Real-Time Multiplex PCR Analysis in Infectious Uveitis. Semin Ophthalmol. 2019;34(4):252-255.  [PMID:31177936]

    Comment: Review of multiplex PCR for evaluation of infectious uveitis requires < 0.1 mL or ocular fluid and can identify common pathogens including toxoplasmosis, HSV, VZV, and CMV.

  4. Robert-Gangneux F, Meroni V, Dupont D, et al. Toxoplasmosis in Transplant Recipients, Europe, 2010-2014. Emerg Infect Dis. 2018;24(8):1497-1504.  [PMID:30014843]

    Comment: Survey data collected from 46 centers in 11 countries included a mean number of allo- (1,016) and auto-HSCT (1,524) procedures as well as heart (155), kidney (1,286), and liver (622) transplants. From 2010-2014, 87 cases reported including cerebral, disseminated, or pulmonary toxoplasmosis in 42 patients (48%, severe), ocular or fever in 14 (16%), and asymptomatic or diagnosed by PCR in 31 (36%). Authors report serologic screening as routine for HSCT and SOT donors. Most centers screened HSCT and SOT recipients. All allo-HSCT recipients received TMP-SMX prophylaxis for at least 6 months post-transplant, and some centers conducted serologic follow-up for Toxoplasma, esp. for heart transplant with a serologic mismatch (D+/R-). PCR is an essential tool for diagnosing infection. Authors conclude that in SOT (D+/R-), TMP-SMX given for at least a year may improve survival.
    Rating: Important

  5. Opsteegh M, Kortbeek TM, Havelaar AH, et al. Intervention strategies to reduce human Toxoplasma gondii disease burden. Clin Infect Dis. 2015;60(1):101-7.  [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.

  6. Jones JL, Bonetti V, Holland GN, et al. Ocular toxoplasmosis in the United States: recent and remote infections. Clin Infect Dis. 2015;60(2):271-3.  [PMID:25301214]

    Comment: Survey of T. gondii Ab+ serum samples from 205 patients diagnosed with ocular toxoplasmosis 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 percentage of the population (>10%) than previously believed.
    Rating: Important

  7. Tamaddon L, Mostafavi SA, Karkhane R, et al. Design and development of intraocular polymeric implant systems for long-term controlled-release of clindamycin phosphate for toxoplasmic retinochoroiditis. Adv Biomed Res. 2015;4:32.  [PMID:25709997]

    Comment: In vitro drug release kinetics described for intraocular 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 intravitreal injections.
    Rating: Important

  8. Wallon M, Peyron F, Cornu C, et al. Congenital toxoplasma infection: monthly prenatal screening decreases transmission rate and improves clinical outcome at age 3 years. Clin Infect Dis. 2013;56(9):1223-31.  [PMID:23362291]

    Comment: An observational cohort of 2048 pregnant women diagnosed with acute Toxoplasma infections at a reference lab in Lyon, France. The majority (93%) received treatment. Risk of congenital 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

  9. Jones JL, Dubey JP. Foodborne toxoplasmosis. Clin Infect Dis. 2012;55(6):845-51.  [PMID:22618566]

    Comment: Authors emphasize the foodborne transmission of T gondii. Commercial processing of meat i.e., cooking, freezing, salting, and injecting with salts and water, kills tissue cysts. However, increased demand for ’free-range’ pork and chicken increases the prevalence of T gondii in the food supply. Antibodies to T gondii are detectable in goat meat and venison (Table 1). Raw oysters, mussels, and clams pose an infection risk. Cooking meats to recommended temperature prevent toxoplasmosis: whole cuts to 150’ with 3-minute rest, ground meat and wild game meat to 160’, and poultry to 165’.
    Rating: Important

  10. Demar M, Hommel D, Djossou F, et al. Acute toxoplasmoses in immunocompetent patients hospitalized in an intensive care unit in French Guiana. Clin Microbiol Infect. 2012;18(7):E221-31.  [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 the Amazon basin are more aggressive and result in severe pulmonary disease more often than strains isolated in Europe and North America.
    Rating: Important

  11. Boyer K, Hill D, Mui E, et al. Unrecognized ingestion of Toxoplasma gondii oocysts leads to congenital toxoplasmosis and causes epidemics in North America. Clin Infect Dis. 2011;53(11):1081-9.  [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 a frequent and unrecognized source of infection. Furthermore, the 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

  12. Lasave AF, Díaz-Llopis M, Muccioli C, et al. Intravitreal clindamycin and dexamethasone for zone 1 toxoplasmic retinochoroiditis at twenty-four months. Ophthalmology. 2010;117(9):1831-8.  [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.

  13. Pappas G, Roussos N, Falagas ME. Toxoplasmosis snapshots: global status of Toxoplasma gondii seroprevalence and implications for pregnancy and congenital toxoplasmosis. Int J Parasitol. 2009;39(12):1385-94.  [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 individuals of the 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

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Last updated: September 6, 2019