Toxoplasmosis

Definition, Etiology, PathogenesisTop

Toxoplasmosis is an inflammatory protozoal zoonosis, which affects multiple organs and systems, including the mononuclear phagocyte system, skeletal muscles, central nervous system (CNS), and retina.

1. Etiologic agent: Toxoplasma gondii, an intracellular parasite with a complex life cycle. It has 3 stages of development: tachyzoite, tissue cyst (containing bradyzoites), and oocyst. Sexual reproduction of the parasite occurs in the intestinal epithelium of the definitive host, which may be a domestic cat or a feline. Asexual reproduction takes place in tissues of intermediate hosts: mammals (including humans) and certain avian species. In an immunocompetent person the infection results in the formation of tissue cysts (predominantly in muscles and the brain), which persist for life and contain live, slowly replicating parasites.

2. Reservoir and transmission: The reservoirs for T gondii in the natural environment are cats and other felines. Humans become infected through:

1) Food (vegetables, fruits), water, and hands contaminated with oocysts from cat feces.

2) Ingestion of raw or undercooked meat of infected animals containing protozoan cysts (most frequently pork or lamb/mutton).

3) Transfer of tachyzoites through the placenta during parasitemia (vertical transmission, occurs almost always in the course of primary infection).

4) Accidental contact with tachyzoites (rare; this may include transfusion of blood or blood products, mainly granulocyte concentrates, as well as organ transplant and laboratory-acquired infections).

5) After primary toxoplasmosis, during immunosuppression, a reactivation of the infection as a result of rupture of tissue cysts and transformation of dormant forms into invasive tachyzoites (endogenous invasion) is possible.

3. Epidemiology: Toxoplasmosis is one of the most common parasitic zoonoses, with a worldwide endemic prevalence. Seronegative pregnant women are a particularly important risk group due to the severe course of intrauterine infection. The rates of Toxoplasma seropositivity vary according to the geographic region and range from 3% to 81% in women of reproductive age. Seroprevalence in the United States is declining (<10% in 2010)Evidence 1Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. Jones JL, Kruszon-Moran D, Rivera HN, Price C, Wilkins PP. Toxoplasma gondii seroprevalence in the United States 2009-2010 and comparison with the past two decades. Am J Trop Med Hyg. 2014 Jun;90(6):1135-9. doi: 10.4269/ajtmh.14-0013. Epub 2014 Apr 7. PMID: 24710615; PMCID: PMC4047742.; some areas in Northern Canada have a higher rate of seroprevalence (60% seropositivity in Nunavik).Evidence 2Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness (data >15 years old). Messier V, Lévesque B, Proulx JF, et al. Seroprevalence of Toxoplasma gondii among Nunavik Inuit (Canada). Zoonoses Public Health. 2009 May;56(4):188-97. doi: 10.1111/j.1863-2378.2008.01177.x. Epub 2008 Sep 22. PMID: 18811673.

Risk factors for infection: Contact with food and water contaminated with cat feces, consumption of raw meat (eg, steak tartare) and unpasteurized milk, contact with cats and contaminated soil (garden, potted plants).

Risk factors for a severe course of the disease (disseminated, ocular, or CNS toxoplasmosis): Immunosuppression of any cause, particularly in patients after organ transplant; immunosuppressive treatment for other conditions; HIV infection; early gestation intrauterine infection.

4. Incubation and contagious period: The incubation period for acquired toxoplasmosis is from 2 weeks to 2 months (average, 4 weeks). Parasitemia may last for 1 to 3 weeks. The risk of infection being transmitted to the fetus is low (3%-9%) if infection is acquired in the first trimester, but this rises to ~40% in the second trimester and to ~70% if the mother is infected in the third trimester.Evidence 3Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. Dunn D, Wallon M, Peyron F, Petersen E, Peckham C, Gilbert R. Mother-to-child transmission of toxoplasmosis: risk estimates for clinical counselling. Lancet. 1999 May 29;353(9167):1829-33. doi: 10.1016/S0140-6736(98)08220-8. PMID: 10359407. Person-to-person spread has not been described.

Clinical Features and Natural HistoryTop

Clinical features depend on the stage of the protozoa, source of infection, virulence of the infecting strain, immunocompetence of the patient, and severity of the invasion. In immunocompetent individuals toxoplasmosis is usually asymptomatic or manifests as limited symptoms only (~80%-90% of cases).

1. Lymphadenopathy: The most common presentation in immunocompetent individuals. It most frequently involves the cervical lymph nodes located along the sternocleidomastoid muscle or posterior and occipital lymph nodes; generalized lymphadenopathy is less common. The lymph nodes are up to 3 cm in diameter; they are usually nontender and are not purulent. Sometimes influenza-like signs and symptoms may be observed. In one-third of patients the clinical presentation is similar to mononucleosis (see Infectious Mononucleosis).

2. Ocular toxoplasmosis: Progressive chorioretinitis, which can occur in immunocompromised or immunocompetent individuals. It manifests primarily as ocular pain and visual loss.

3. Generalized toxoplasmosis: Very rare in immunocompetent individuals, predominantly affects immunosuppressed patients. Clinical manifestations involve ≥1 internal organ (myocarditis, pneumonia, pleuritis, hepatitis with hepatomegaly, splenomegaly, bone marrow infiltration) and/or the CNS (encephalitis, meningitis, myelitis, polyneuritis).

4. Congenital toxoplasmosis: Intrauterine infection caused by T gondii parasitemia that occurred in the course of pregnancy or shortly before conception. Possible manifestations include miscarriage, fetal death, symptomatic intrauterine and neonatal infection (generalized form with very severe developmental sequelae), generalized or visceral toxoplasmosis developing in early infancy, reactivation of infection in adolescence or early adulthood, asymptomatic course or only minor symptoms. Acquisition of infection early in gestation is associated with increased severity of infection, such as fetal death or severe neurologic deficits. Untreated infection (including asymptomatic forms) may result in reactivation later in life (usually the second and third decades), frequently manifesting as ocular toxoplasmosis.

DiagnosisTop

Diagnostic Tests

1. Tests that can support the diagnosis of acute Toxoplasma infection include:

1) Serology: Positive specific serum antibodies in immunocompetent patients.

a) IgM: Appear within 1 week of invasion; the levels peak after 1 month and usually disappear after 6 to 9 months, but they may persist for several months or years after infection.

b) IgA: Their presence indicates a recent infection. They disappear earlier than IgM. The assay is less available but may be useful in diagnosing infections during pregnancy and congenital infections.

c) IgG: Peak levels are observed within 2 to 3 months of invasion, while the antibodies persist for life. In patients in whom establishing the time of infection is necessary (eg, pregnant women), IgG avidity (strength of antigen binding) testing is performed; low-avidity antibodies indicate the acute phase of toxoplasmosis, whereas high-avidity antibodies indicate invasion ≥20 weeks earlier.

2) Identification of the parasite in immunosuppressed patients, children in utero, newborns, and infants with an immature immune system (specimens: blood, cerebrospinal fluid, amniotic fluid, bronchoalveolar lavage, intraocular fluid, or biopsy specimens/surgical samples of involved tissues or organs): Isolation of the parasite (culture and microscopic examination), detection of parasite antigens or genetic material (polymerase chain reaction [PCR]).

2. Other diagnostic tests: Fundoscopy is mandatory in every patient with suspected toxoplasmosis. In patients with suspected CNS involvement, neuroimaging (computed tomography [CT], magnetic resonance imaging [MRI]) is necessary, as it may reveal characteristic irregular focal lesions.

Diagnostic Criteria

Acquired toxoplasmosis (including toxoplasmosis in pregnant women):

1) Specific IgG seroconversion; or

2) Clinical features typical for toxoplasmosis, detection of specific serum IgA/IgM, and high levels of low-avidity specific IgG (<20%); or

3) Epithelioid cells and lymphoid follicular hyperplasia found on histologic examination of an enlarged lymph node, presence of specific IgM, and increasing or elevated levels of specific IgG; or

4) Isolation of the parasite in cultures or detection of its genetic material in blood, body fluids, or tissues.

Diagnosis in immunosuppressed patients is often based on the clinical features and characteristic morphology of space-occupying lesions in the brain seen on imaging studies. Serologic studies may not be reliable in this population.

Differential Diagnosis

Differential diagnosis of acquired toxoplasmosis should include infectious mononucleosis, cytomegalovirus (CMV) infection, Hodgkin lymphoma, non-Hodgkin lymphoma, tuberculosis, sarcoidosis, and HIV infection.

TreatmentTop

Immunocompetent patients with asymptomatic or mild acquired toxoplasmosis usually require no antiparasitic treatment.

1. Acute acquired toxoplasmosisEvidence 4Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness (most evidence extrapolated from HIV population). Dunay IR, Gajurel K, Dhakal R, Liesenfeld O, Montoya JG. Treatment of Toxoplasmosis: Historical Perspective, Animal Models, and Current Clinical Practice. Clin Microbiol Rev. 2018 Sep 12;31(4):e00057-17. doi: 10.1128/CMR.00057-17. PMID: 30209035; PMCID: PMC6148195.: In the case of severe systemic or organ-related symptoms, start pyrimethamine 100 mg loading dose followed by 50 mg once daily combined with sulfadiazine 1 g every 6 hours for 2 to 4 weeks. In the course of pyrimethamine treatment, administer leucovorin (INN folinic acid) 25 mg daily to prevent bone marrow suppression. Trimethoprim/sulfamethoxazole can be used as an alternative regimen. In patients with sulfadiazine intolerance use clindamycin in combination with pyrimethamine and leucovorin (treatment should be conducted in specialized centers).

2. Ocular toxoplasmosis: The decision to treat depends on the degree of ocular involvement, immune status of the patient, and most importantly the status of the ocular lesion (active vs inactive). Treatment is as in acute toxoplasmosis (see above), initially conducted for 4 to 6 weeks in a specialized center under close supervision of an ophthalmologist. Alternatives to oral antimicrobial therapy include intravitreal injections of clindamycin and dexamethasone. Adjunctive treatment with topical or systemic glucocorticoids is controversial but widely practiced. The consensus is to delay commencement of glucocorticoids until day 1 to 7 of antimicrobial therapy.Evidence 5Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision, heterogeneity, and use of observational data. Ozgonul C, Besirli CG. Recent Developments in the Diagnosis and Treatment of Ocular Toxoplasmosis. Ophthalmic Res. 2017;57(1):1-12. doi: 10.1159/000449169. Epub 2016 Oct 11. PMID: 27723657. Casoy J, Nascimento H, Silva LMP, et al. Effectiveness of Treatments for Ocular Toxoplasmosis. Ocul Immunol Inflamm. 2020;28(2):249-255. doi: 10.1080/09273948.2019.1569242. Epub 2019 Feb 26. PMID: 30806556.

3. Infection in immunosuppressed patients, including patients living with HIV: In the case of symptomatic reactivation of a prior infection, treatment with pyrimethamine and sulfadiazine is usually the first choice; this is particularly relevant in HIV-related toxoplasmic encephalitis. Treatment is at higher doses than in immunocompetent individuals: pyrimethamine 200 mg loading dose followed by 75 mg once daily (or 50 mg for a body weight <60 kg) and sulfadiazine 1.5 g every 6 hours (or 1g every 6 hours for a body weight <60 kg).Evidence 6Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. Katlama C, De Wit S, O'Doherty E, Van Glabeke M, Clumeck N. Pyrimethamine-clindamycin vs. pyrimethamine-sulfadiazine as acute and long-term therapy for toxoplasmic encephalitis in patients with AIDS. Clin Infect Dis. 1996 Feb;22(2):268-75. doi: 10.1093/clinids/22.2.268. PMID: 8838183. Dannemann B, McCutchan JA, Israelski D, et al. Treatment of toxoplasmic encephalitis in patients with AIDS. A randomized trial comparing pyrimethamine plus clindamycin to pyrimethamine plus sulfadiazine. The California Collaborative Treatment Group. Ann Intern Med. 1992 Jan 1;116(1):33-43. doi: 10.7326/0003-4819-116-1-33. PMID: 1727093. Leport C, Raffi F, Matheron S, et al. Treatment of central nervous system toxoplasmosis with pyrimethamine/sulfadiazine combination in 35 patients with the acquired immunodeficiency syndrome. Efficacy of long-term continuous therapy. Am J Med. 1988 Jan;84(1):94-100. doi: 10.1016/0002-9343(88)90014-9. PMID: 3337134. Secondary prophylaxis at lower doses is continued until immune reconstitution (CD4+ count ≥0.2×109/L for 6 months).Evidence 7Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias and indirectness. Miro JM, Lopez JC, Podzamczer D, et al; GESIDA 04/98 Study Group. Discontinuation of primary and secondary Toxoplasma gondii prophylaxis is safe in HIV-infected patients after immunological restoration with highly active antiretroviral therapy: results of an open, randomized, multicenter clinical trial. Clin Infect Dis. 2006 Jul 1;43(1):79-89. doi: 10.1086/504872. Epub 2006 May 31. Erratum in: Clin Infect Dis. 2006 Sep 1;43(5):671. PMID: 16758422. Alternative regimens, such as pyrimethamine and clindamycin or trimethoprim/sulfamethoxazole, are options if there is a contraindication to first-line therapy.Evidence 8Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias, indirectness, imprecision, and heterogeneity. Dunay IR, Gajurel K, Dhakal R, Liesenfeld O, Montoya JG. Treatment of Toxoplasmosis: Historical Perspective, Animal Models, and Current Clinical Practice. Clin Microbiol Rev. 2018 Sep 12;31(4):e00057-17. doi: 10.1128/CMR.00057-17. PMID: 30209035; PMCID: PMC6148195. Wei HX, Wei SS, Lindsay DS, Peng HJ. A Systematic Review and Meta-Analysis of the Efficacy of Anti-Toxoplasma gondii Medicines in Humans. PLoS One. 2015 Sep 22;10(9):e0138204. doi: 10.1371/journal.pone.0138204. PMID: 26394212; PMCID: PMC4578932. Management should be undertaken with specialist input.

4. Primary infection during pregnancy: Diagnosis of infection in pregnancy should be made in consultation with specialists. Diagnosis of acute infection in pregnancy warrants prophylaxis of vertical transmission to the fetus. Prophylaxis of congenital toxoplasmosis involves the use of oral spiramycin 1 g every 8 hours until confirmation of fetal parasitic invasion (positive PCR on amniocentesis or suggestive features on ultrasonography) or birth. Upon confirmation of fetal invasion, start pyrimethamine combined with sulfadiazine and leucovorin (pyrimethamine 50 mg daily, sulfadiazine 1 g every 8 hours) and continue until birth.

In the case of primary infection of T gondii in the second half of pregnancy (after 18 weeks), it is recommended to omit pharmacologic prophylaxis with spiramycin and immediately start intensive maternal and fetal treatment with pyrimethamine and sulfadiazine together with leucovorin supplementation. Treatment should be conducted at a specialist center.Evidence 9Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias, indirectness, imprecision, and heterogeneity. Dunay IR, Gajurel K, Dhakal R, Liesenfeld O, Montoya JG. Treatment of Toxoplasmosis: Historical Perspective, Animal Models, and Current Clinical Practice. Clin Microbiol Rev. 2018 Sep 12;31(4):e00057-17. doi: 10.1128/CMR.00057-17. PMID: 30209035; PMCID: PMC6148195. Peyron F, L'ollivier C, Mandelbrot L, et al. Maternal and Congenital Toxoplasmosis: Diagnosis and Treatment Recommendations of a French Multidisciplinary Working Group. Pathogens. 2019 Feb 18;8(1):24. doi: 10.3390/pathogens8010024. PMID: 30781652; PMCID: PMC6470622. Wei HX, Wei SS, Lindsay DS, Peng HJ. A Systematic Review and Meta-Analysis of the Efficacy of Anti-Toxoplasma gondii Medicines in Humans. PLoS One. 2015 Sep 22;10(9):e0138204. doi: 10.1371/journal.pone.0138204. PMID: 26394212; PMCID: PMC4578932. Paquet C, Yudin MH; Society of Obstetricians and Gynaecologists of Canada. Toxoplasmosis in pregnancy: prevention, screening, and treatment. J Obstet Gynaecol Can. 2013 Jan;35(1):78-81. English, French. doi: 10.1016/s1701-2163(15)31053-7. PMID: 23343802.

Note that hematologic adverse outcome events have been reported in the literature across all manifestations (ocular toxoplasmosis, toxoplasmic encephalitis, congenital toxoplasmosis), thus underscoring the importance of monitoring blood for leukopenia and thrombocytopenia in patients receiving pyrimethamine plus other drugs to treat toxoplasmosis.Evidence 10Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias and inclusion of nonexperimental evidence). Ben-Harari RR, Goodwin E, Casoy J. Adverse Event Profile of Pyrimethamine-Based Therapy in Toxoplasmosis: A Systematic Review. Drugs R D. 2017 Dec;17(4):523-544. doi: 10.1007/s40268-017-0206-8. PMID: 28879584; PMCID: PMC5694419.

Follow-UpTop

In the course of treatment monitor the complete blood count (CBC) on a regular basis (initially twice weekly) due to the significant risk of developing leukopenia and thrombocytopenia. In the case of deteriorating visual acuity, perform repeated fundoscopy.

ComplicationsTop

1. Congenital toxoplasmosis: Psychomotor retardation, hydrocephalus (increased intracranial pressure), epilepsy, cataract, retinal detachment.

2. Ocular toxoplasmosis: Endophthalmitis, permanent visual-field loss, amblyopia, loss of vision.

3. Toxoplasmosis in immunocompromised patients: Multiple organ failure, transplant rejection, neurologic symptoms.

PrognosisTop

The prognosis is good in the case of acquired toxoplasmosis in immunocompetent patients and uncertain in immunocompromised patients and children with congenital infection. Total mortality rates among patients with congenital toxoplasmosis can reach up to 10%.

PreventionTop

1. Adherence to the basic principles of hygiene and nutrition:

1) Avoid consumption or tasting of raw or undercooked meats or cold cuts and raw milk. Thoroughly wash hands and kitchen utensils after contact with such foods.

2) Thoroughly rinse fruits and vegetables prior to consumption.

3) Use protective gloves (rubber or latex) for gardening and field work.

4) Clean cat litter boxes on a daily basis and thoroughly wash hands after contact with a cat or objects contaminated with cat feces (if possible, pregnant women should refrain from performing these tasks).

2. Serology screening in pregnancy is not indicated in Canada due to the low incidence of acute infections, lack of a highly specific diagnostic test, and high cost and burden of repeated serum sampling. Testing should be performed in symptomatic individuals or if there is concern regarding fetal infection due to ultrasound abnormalities.

3. Primary prophylaxis is recommended in seropositive persons with HIV and CD4+ counts <0.1×109/L.Evidence 11Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of data. Carr A, Tindall B, Brew BJ, et al. Low-dose trimethoprim-sulfamethoxazole prophylaxis for toxoplasmic encephalitis in patients with AIDS. Ann Intern Med. 1992 Jul 15;117(2):106-11. doi: 10.7326/0003-4819-117-2-106. PMID: 1351371.

4. Toxoplasmosis is not a notifiable disease in Canada.