Toxoplasma/Toxoplasmosis

Toxoplasmosis is an infectious disease caused by Toxoplasma gondii, an obligate intracellular protozoan parasite. Felines are the definitive host, but transmission to humans can occur through contact with cat feces or the consumption of contaminated foods. The clinical presentation and complications depend on the host’s immune status. Patients who are immunocompetent usually have no symptoms, whereas those who are immunocompromised may develop CNS toxoplasmosis or chorioretinitis. The diagnosis is often made based on serology or PCR. Patients who are immunocompetent may not need any treatment. Patients who are immunocompromised or those with severe disease may require combination therapy with pyrimethamine, sulfadiazine, and leucovorin.

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General Characteristics and Epidemiology

General features of Toxoplasma

General characteristics:

  • Obligate intracellular parasite
  • Protozoan parasite

Morphologic forms:

  • Oocyst: 
    • Shed in feline feces
    • Takes 1–5 days to sporulate in the environment and become infective
  • Tachyzoite (also called trophozoite):
    • Obligate intracellular form 
    • Crescent-shaped form with a central nucleus
    • Responsible for cell invasion and clinical disease
    • Multiplies rapidly
  • Bradyzoite: 
    • Quiescent
    • Forms a thick wall around itself (tissue cyst)
    • Resistant to digestive enzymes
    • Killed by freezing and normal cooking temperatures

Clinically relevant species

Toxoplasmosis is caused by Toxoplasma gondii.

Epidemiology

  • Found worldwide, but more common in tropical regions
  • 225,000 cases reported each year in the United States
  • Approximately 50% of individuals have antibodies against T. gondii:
    • Approximately 11% of the population > 6 years of age in the United States
    • Up to 78% of the population in some areas of Brazil

Pathogenesis

Hosts

  • Felines are the only definitive host.
  • Infections can occur in a wide range of vertebrate intermediate hosts (including humans).

Transmission

  • Oral route: 
    • Ingestion of oocysts passed in the feces of infected felines 
    • Ingestion of infected meat that is raw or undercooked (tissue cyst form)
  • Blood transfusion or organ transplantation 
  • Vertical transmission

Life cycle and pathophysiology

Life cycle:

  • Oocysts are shed in the cat’s feces → ingested by an intermediate host (e.g., mammals, birds)
  • Oocysts transform into tachyzoites → localize in neural and muscle tissues → develop into tissue cysts
  • Cat consumes an infected intermediate host’s tissue → organism undergoes sexual cycle → cycle continues 

Life cycle and pathophysiology in humans:

  • Transmission to a human host → bradyzoites released from cysts (or sporozoites from oocysts)
  • Transformation to tachyzoites → multiply rapidly in GI cells → rupture cells
  • Transported in the lymphatics and disseminate in the bloodstream to: 
    • Skeletal muscle
    • Myocardium
    • Brain
    • Eyes
  • Immune system generally controls the replication of tachyzoites.
  • Bradyzoites develop cysts and remain dormant → can remain dormant for years
Life cycle of toxoplasma gondii

Life cycle of Toxosplasma gondii

Image: “3421” by CDC/Alexander J. da Silva, PhD; Melanie Moser. License: Public Domain

Clinical Presentation

The clinical presentation of toxoplasmosis can vary depending on the host’s immune function and organs involved. The following table summarizes the various diseases:

Table: Clinical presentations of toxoplasmosis
HostDiseasePresentation
Immunocompetent hostSubclinical infection (approximately 90% of cases)Asymptomatic
Acute systemic diseaseCommon signs and symptoms:
  • Fever
  • Sore throat
  • Bilateral nontender cervical lymphadenopathy
  • Malaise
  • Nonpruritic maculopapular rash
  • Hepatosplenomegaly
  • Headache
Uncommon manifestations:
  • Pneumonitis
  • Myocarditis
  • Hepatitis
  • Posterior uveitis
  • Polymyositis
  • Encephalitis
Immunocompromised host (e.g., AIDS)CNS toxoplasmosis (AIDS-defining illness, CD4 count < 100 cells/µL)
  • Fever
  • Headache
  • Focal neurologic deficits
  • Mental status changes
  • Seizures
ChorioretinitisSymptoms:
  • Floaters
  • Blurred or loss of vision
  • Eye pain
Fundoscopic findings:
  • Raised yellow-white cotton lesions
  • Nonvascular distribution
Pneumonitis
  • Fever
  • Dyspnea
  • Nonproductive cough
Fetus, newborn, or infantCongenital toxoplasmosisClassic triad:
  • Chorioretinitis
  • Hydrocephalus
  • Diffuse intracranial calcifications
Signs and symptoms:
  • Fever
  • Hepatosplenomegaly
  • Lymphadenopathy
  • Jaundice
  • Anemia and thrombocytopenia
  • Delayed growth
  • Petechiae and purpura (“blueberry muffin” rash)
  • Macrocephaly
  • Pneumonitis
  • Seizures
  • Sensorineural hearing loss
CD4: cluster of differentiation 4
Toxoplasma retinochoroiditis

Fundoscopy of Toxoplasma chorioretinitis:
Note the yellow-white cotton lesions in both the right eye (A) and left eye (B).

Image: “Retinochoroiditis” by Department of Ophthalmology and Visual Sciences, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, NY 10467, USA. License: CC BY 2.0

Diagnosis

The diagnostic workup will be guided by the patient’s clinical presentation.

Laboratory evaluation

  • Serologic testing (ELISA):
    • IgM antibodies: 
      • Appear within 1 week of symptom onset
      • A positive test indicates active infection.
    • IgG antibodies:
      • Appear within 2 weeks of symptom onset
      • Persist for life
  • PCR:
    • Detects parasite DNA
    • Samples can be obtained from:
      • Blood
      • CSF
      • Aqueous humor
      • Bronchoalveolar lavage
  • Supporting laboratory studies:
    • Negative heterophile antibody test → rules out mononucleosis
    • Lymphocytosis (with or without atypical cells)
    • Mild transaminitis

Histopathology

  • Provides a definitive diagnosis, but rarely required
  • Lymph node findings:
    • Reactive follicular hyperplasia
    • Irregular clusters of tissue macrophages with eosinophilic cytoplasm
  • Brain findings:
    • Patchy, diffuse encephalitis
    • Cyst lesions
    • Necrotic regions
    • Granulomas
    • Lymphocytic vasculitis
  • Ocular findings:
    • Segmental panophthalmitis
    • Necrosis
    • Tissue cysts and tachyzoites
Neurotoxoplasmosis histology

Photomicrograph of a Toxoplasma gondii tissue cyst in a brain tissue specimen

Image: “16543” by CDC/Dr. Martin Hicklin. License: Public Domain

Imaging

Brain imaging may be performed if CNS or congenital toxoplasmosis is suspected.

  • Options:
    • CT
    • MRI
  • Findings in CNS toxoplasmosis:
    • Single or multiple ring-enhancing lesions
    • Inflammatory changes
  • Findings in congenital toxoplasmosis:
    • Scattered calcifications 
    • Hydrocephalus 
    • Cortical atrophy

Management and Prevention

Management

Patients who are immunocompetent typically do not require treatment. However, treatment is needed for patients who are immunocompromised, pregnant, or with severe or prolonged symptoms.

  • Combination medical therapy:
    • Pyrimethamine (inhibits dihydrofolate reductase)
    • Sulfadiazine (inhibits dihydropteroate synthetase)
    • Leucovorin (folinic acid, prevents folic acid deficiency)
  • Corticosteroids may be added in CNS toxoplasmosis to reduce cerebral edema if mass effect is present.
  • Ensure that patients with AIDS are started on antiretroviral therapy.

Prevention and prophylaxis

  • General advice:
    • Wash hands after handling raw meat or cat litter.
    • Thoroughly cook meat.
  • Pregnant patients:
    • Routine antibody screening in pregnant women is not recommended.
    • Avoid cats.
    • Do not clean litter boxes (if unavoidable, wear gloves).
  • Patients with AIDS: long-term sulfamethoxazole-trimethoprim when CD4 < 100 cells/µL

Differential Diagnosis

  • Infectious mononucleosis: a disease caused by EBV that is characterized by fever, fatigue, lymphadenopathy, and pharyngitis. Atypical lymphocytosis may be seen. The diagnosis is based on clinical features and tests, such as a positive heterophile antibody test or serology. Management is supportive. 
  • CMV mononucleosis: a disease caused by CMV. Patients may present with fevers, lymphadenopathy, hepatitis, and atypical lymphocytosis. However, pharyngitis is absent. Positive CMV serologic testing provides the diagnosis. The disease is self-limiting.
  • Acute human immunodeficiency virus (HIV) infection: a sexually transmitted or blood-borne disease caused by HIV. The presentation of HIV is marked by constitutional symptoms such as lymphadenopathy and fever. Further progression may lead to opportunistic infections and malignancies. Diagnosis is by enzyme immunoassay. Additional tests include HIV viral load determination, genotyping, and CD4+ T lymphocyte count. Immediate treatment with combination antiretroviral therapy is recommended.
  • Tularemia: a rare infection caused by Francisella tularensis acquired by contact with animal tissue, ticks, or biting flies. The infection manifests as a papule, followed by fever, headache, and suppurative lymphadenopathy. Tularemia may have multiorgan involvement. Diagnosis is based on culture of blood and infected tissues. Treatment is with antibiotics.
  • Cat-scratch disease: an infection caused by Bartonella henselae, a gram-negative bacillus. Patients usually present with fever, weight loss, and tender lymphadenopathy after being bitten or scratched by a cat. The diagnosis is confirmed with serology or PCR. Symptomatic treatment is recommended and azithromycin is given for severe illness.
  • Extrapulmonary tuberculosis: a disseminated mycobacterial infection. The presentation of extrapulmonary tuberculosis includes meningitis, pericarditis, lymphadenitis, and liver infection, and can vary depending on the site involved. The diagnosis is based on the detection of acid-fast bacilli by culturing body fluids or tissue samples. Treatment involves combination therapy with isoniazid, rifampin, pyrazinamide, and ethambutol.
  • Hodgkin disease: a malignancy of B lymphocytes within the lymph nodes. Patients present with lymphadenopathy, night sweats, weight loss, fever, splenomegaly, and hepatomegaly. Diagnostic tests include lymph node histological analysis, blood tests, CT, and PET. Management includes chemotherapy and radiotherapy.
  • Neurocysticercosis: an infection caused by ingestion of Taenia solium eggs. Cysts can form anywhere in the CNS and cause personality changes, seizures, focal neurologic deficits, or signs of intracranial hypertension. The diagnosis is usually made based on the “swiss cheese” appearance of the brain on MRI or CT. Serology may also be useful. Management is controversial, but may include steroids, anthelmintic therapy, and neurosurgical consultation.
  • Intracranial tumors: a benign or malignant growth of cells in the brain that present as headache, unexplained nausea or vomiting, blurred vision, and difficulty in speech or hearing. The diagnosis is made with a neurologic examination, imaging (MRI or CT), and, sometimes, biopsy. Management includes radiation, chemotherapy, and/or surgery.
  • Brain abscess: a collection of pus in the brain parenchyma due to an infection. A brain abscess presents with fever, headaches, seizures, nausea, and vomiting. The diagnosis is mainly based on imaging, as it is difficult to arrive at a definitive diagnosis based on clinical presentation alone. Management includes antibiotic therapy and surgery to drain the abscess.

References

  1. Petersen, E. (2019). Toxoplasmosis: Acute systemic disease. In Mitty, J. (Ed.), UpToDate. Accessed March 25, 2021, from https://www.uptodate.com/contents/toxoplasmosis-acute-systemic-disease
  2. Petersen, E., Mandelbrot, L. (2021). Toxoplasmosis in pregnancy. In Barss, V.A., and Mitty, J. (Eds.), UpToDate. Retrieved April 22, 2021, from https://www.uptodate.com/contents/toxoplasmosis-and-pregnancy
  3. Guerina, N.G., Marquez, L. (2020). Congenital toxoplasmosis: Clinical features and diagnosis. In Armsby, C. (Ed.), UpToDate. Retrieved April 22, 2021, from https://www.uptodate.com/contents/congenital-toxoplasmosis-clinical-features-and-diagnosis
  4. Gandhi, R.T. (2021). Toxoplasmosis in patients with HIV. In Mitty, J. (Ed.), UpToDate. Retrieved April 22, 2021, from https://www.uptodate.com/contents/toxoplasmosis-in-patients-with-hiv
  5. Schwartzman, J.D., Petersen, E. (2019). Diagnostic testing for toxoplasmosis infection. In Mitty, J. (Ed.), UpToDate. Retrieved April 22, 2021, from https://www.uptodate.com/contents/diagnostic-testing-for-toxoplasmosis-infection
  6. Madireddy, S., Rivas Chacon, E.D., Mangat, R. (2020). Toxoplasmosis. [online] StatPearls. Retrieved April 22, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK563286/
  7. Centers for Disease Control and Prevention (2020). Parasites – toxoplasmosis (toxoplasma infection). Retrieved April 22, 2021, from https://www.cdc.gov/parasites/toxoplasmosis/biology.html
  8. The Australian Society for Parasitology Inc. (n.d.). Toxoplasma. Retrieved April 22, 2021, from http://parasite.org.au/para-site/text/toxoplasma-text.html
  9. Hokelek, M. (2019). Toxoplasmosis. In Bronze, M.S. (Ed.), Medscape. Retrieved April 22, 2021, from https://emedicine.medscape.com/article/229969-overview
  10. McCabe, R.E., et al. (1987). Clinical spectrum in 107 cases of toxoplasmic lymphadenopathy. Rev Infect Dis, 9(4), 754–74. https://pubmed.ncbi.nlm.nih.gov/3326123/
  11. Jones, J.L, et al. Toxoplasma gondii infection in the United States 1999-2004 decline from the prior decade. Am J Trop Med Hyg. 2007;77(3):405. https://pubmed.ncbi.nlm.nih.gov/17827351/

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