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Toxoplasmosis


Toxoplasmosis

Article Author:
Sowmya Madireddy
Article Author:
Emanuel Rivas Chacon
Article Editor:
Rupinder Mangat
Updated:
9/25/2020 6:39:41 PM
For CME on this topic:
Toxoplasmosis CME
PubMed Link:
Toxoplasmosis

Introduction

Toxoplasmosis is caused by the parasite Toxoplasma gondii, an obligate intracellular protozoan. Although many people are infected worldwide, the disease is uncommon, as most infections in humans are asymptomatic. This organism does, however, have the potential to cause significant disease in infants and immunocompromised individuals through primary infection or reactivation of latent infection. Transmission of infection often occurs through the ingestion of tissue cysts via improperly cooked/raw meat, or ingestion of oocysts via contaminated food and water. Vertical transmission and transmission through organ transplantation can also occur. Treatment is indicated in all immunocompromised patients as well as immunocompetent patients with severe symptoms. The combination of pyrimethamine and sulfadiazine is the preferred regimen for the therapeutic management of toxoplasmosis.

Etiology

T. gondii is an obligate intracellular parasite that infects warm-blooded animals, including humans. It has a complex lifecycle, requiring a definitive host and an intermediate host to complete sexual and asexual cycles respectively. Members of the family Felidae are the only known definitive hosts for this organism. Cats can become infected by ingestion of infected oocysts or tissue cysts via the consumption of intermediate hosts. Infected cats shed millions of unsporulated oocysts in the feces for about 1 to 3 weeks. Oocysts from take 1 to 5 days to transform into infectious oocysts, which can remain infective in the environment for about a year.

When improperly cooked meat or food contaminated with cat feces is ingested, the outer cyst wall surrounding sporozoites and bradyzoites are proteolyzed by gastric juice in the alimentary canal. These uncoated sporozoites and bradyzoites enter the gut epithelium and differentiate into tachyzoites. Tachyzoites are rapidly multiplying forms of T. gondii. Tachyzoites can penetrate any nucleated cell, including dendritic cells, monocytes, and neutrophils resulting in dissemination. With the onset of the host immune response, these tachyzoites are repressed and eventually converted into slow replicating forms termed bradyzoites. Bradyzoites form a thick cyst wall around them, forming a tissue cyst enclosing thousands of bradyzoites. These cysts remain in a dormant form in the immunocompetent host. However, they can get reactivated when the host immune system is compromised. 

Humans can contract T. gondii infection in four ways:[1]

  1. Foodborne transmission - Ingestion of tissue cysts via consumption of undercooked/raw meat
  2. Zoonotic transmission - Ingestion of oocysts via consumption of food and water contaminated with feline feces.
  3. Vertical transmission - Infected mother causes congenital infection through the placenta.
  4. Transmission via organ transplantation or blood transfusion.

Epidemiology

According to the Center for Disease Control and Prevention (CDC), over 11% of the population, over 6 years of age are infected with T. gondii in the United States.[2] Toxoplasmosis is the leading cause of death due to foodborne infections and is one of five neglected parasitic infections in the United States (with the others being Chagas disease, trichomoniasis, toxocariasis, cysticercosis). The prevalence of infection varies both between countries and locally within a country. The various factors that affect prevalence include:

  • High seroprevalence of T. gondii is observed in warm and humid areas as oocysts survive better in these environments. 
  • Areas with livestock as they can be a direct source of infection and a possible reservoir.[3] 
  • Seroprevalence increases with age.[4]

The factors affecting the prevalence of toxoplasmosis in patients with human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) are similar to that of the general population. Patients with AIDS are at risk for developing reactivated disease, particularly when the CD4 count drops below 100 cells/microL.

Pathophysiology

Intracellular growth of tachyzoites results in direct cytopathic effects, cellular inflammation, and necrosis. Type 1 cell-mediated immunity (CMI) is mainly required to control acute and chronic infection of T. gondii. Thus any defects in cell-mediated immunity predispose the host to develop severe manifestations of toxoplasmosis. In response to the damage caused by tachyzoite entry, the gut epithelial cells produce chemokines that act as chemical messengers resulting in the recruitment of dendritic cells (DC), macrophages, and neutrophils to the site of damage. The entry of tachyzoites into these inflammatory cells stimulates the production of interleukin-12 (IL-12). IL-12 induces interferon-gamma (IFN-gamma) synthesis by natural killer (NK) cells and T lymphocytes.

Synthesis of IFN-gamma is required to control acute and chronic infection. Low CD4 counts seen in patients with AIDS result in lower IFN-gamma levels, thereby causing unopposed multiplication of tachyzoites in case of acute infection and reactivation of bradyzoites in latent infection resulting in severe disease (cerebral and extracerebral toxoplasmosis). Though CMI plays a key role in controlling the T. gondii infection, humoral immunity also contributes by synthesizing antibodies, modulating CD4 and CD8 T-cell responses, and amplifying IFN-gamma production involved in CMI.[4]

Histopathology

Patients with toxoplasmosis often present with cervical and/or generalized lymphadenopathy, cerebral encephalitis, and ocular toxoplasmosis. The histological findings of the viscera commonly involved are discussed below:

  • Lymph-node biopsy - The triad of follicular hyperplasia, micro-granulomas, and monocytoid B-cell hyperplasia are highly specific to T. gondii infection.[5]
  • Brain biopsy - Histology usually reveals necrotic areas with patchy diffuse encephalitis, cyst-containing lesions, microglial nodules, granulomas, and lymphocytic vasculitis.[6]
  • Ocular biopsy - Characterized by necrosis in the setting of segmental panophthalmitis with associated tissue cysts and tachyzoites.[7]

Hematoxylin and eosin staining of tissue demonstrate T. gondii parasites (either in the form of tachyzoites or tissue cysts) in both healthy and necrotic areas. These were often noticed to be closer to blood vessels, indicating hematogenous dissemination of infection.[7]

History and Physical

Many patients infected with T. gondii are asymptomatic. However, some immunocompetent patients with acute infection may complain of vague symptoms, including fevers, chills, headaches, pharyngitis, myalgias, rash, or hepatosplenomegaly. More commonly, patients may complain of non-tender cervical lymphadenopathy that can persist for weeks.[8] Immunocompetent individuals who present with fevers and cervical lymphadenopathy should raise suspicion for toxoplasmosis.

Immunosuppressed individuals with severe complications may present with signs and symptoms related to the affected organ. HIV-infected patients typically present with neurological symptoms, although the extracerebral disease can also occur.

  • Cerebral toxoplasmosis usually presents with neurological symptoms based on the region of the brain involved and the number of lesions. Symptoms may include fevers, seizures, headaches, change in vision, altered mental status, focal neurological deficits, cognitive dysfunction, ataxia, and involuntary movements.[9] 
  • Extracerebral toxoplasmosis typically presents as pneumonitis and chorioretinitis; however, heart, gastrointestinal, genitourinary, musculoskeletal, and disseminated disease can also occur.
    • Pneumonitis - patients present with fever, cough, and shortness of breath
    • Chorioretinitis - patients may present with a change in vision, floaters, or ocular pain.

Evaluation

Although biopsy provides a definitive diagnosis, toxoplasmosis can be diagnosed based on non-invasive testing, including labs and imaging.

  • Serological testing - This is the primary diagnostic method to determine infection with Toxoplasma by identifying IgM and IgG antibodies. IgM antibodies are usually detectable from day 5 following infection, reaching maximum levels in 1 to 2 months. IgG antibodies are detectable after 1 to 2 weeks of infection, reaching maximum levels in 3 to 6 months. Toxoplasma IgM antibody testing lacks specificity; thus, serologies can be difficult to interpret. 
  • Molecular testing - T. gondii DNA can be detected by polymerase chain reaction (PCR) in blood and other bodily fluids.
  • Radiological diagnosis - Computed tomography (CT) or magnetic resonance imaging (MRI) findings show multiple hypodense areas with ring-enhancing lesions in the brain. Minimal inflammatory changes seen during the early stages may not be appreciated well on CT; thus, MRI is preferred over CT for diagnosing brain lesions in cerebral toxoplasmosis. Single-photon emission CT or positron emission tomography (PET) scans have high specificity to rule out differential diagnoses.
  • Biopsy - Although this provides a definitive diagnosis by demonstrating tachyzoites and tissue cysts of T. gondii, this is not usually performed. A biopsy is indicated to rule out other differential diagnoses in individuals failing to show clinical or radiological improvement of symptoms within 14 days of starting the therapy.

Treatment / Management

The goal of treatment is to limit parasite multiplication during active infection. Therapeutic treatment is indicated in immunocompetent individuals with severe or prolonged symptoms as well as all immunocompromised patients. In cases of suspected T. gondii infection, empirical therapy based on presumptive diagnosis is preferred rather than waiting for test results. The combination of pyrimethamine (200mg loading dose followed by 50mg daily for patients <60kg and 75mg daily for patients >60kg) and sulfadiazine (1000mg four times a day for patients <60kg and 1500mg four times a day for patients >60kg) is the preferred regimen for treatment. Initial therapy should be continued for 6 weeks and be followed by chronic maintenance therapy.

Folic acid is usually added to the treatment regimen to prevent folic acid deficiency due to sulfadiazine. Steroids are added to the standard regimen to treat patients with cerebral edema and ocular toxoplasmosis.[10][11] Therapeutic management of toxoplasmosis also includes starting antiretroviral therapy for immune reconstitution, usually within 2 weeks of starting anti-toxoplasmosis therapy.[12] 

Prophylactic anti-toxoplasma therapy is started in patients with HIV/AIDS who are T. gondii IgG positive with CD4 cell counts <100 cells/microL. Trimethoprim-sulfamethoxazole is the drug of choice to prevent reactivation of latent infection. Prophylaxis can be discontinued when CD4 count is >200 cells/microL for at least 3 months, and viral load is suppressed.

Differential Diagnosis

  • CNS lymphoma
  • Metastatic brain lesions
  • Progressive multifocal encephalopathy
  • Cerebral tuberculosis
  • Bacterial/fungal brain abscess 
  • Cytomegalovirus
  • Acute HIV infection
  • Herpes simplex encephalitis

Prognosis

Acute toxoplasmosis is typically self-limited in immunocompetent individuals. Prognosis is excellent without any long term effects of infection. Early diagnosis and initiation of empiric treatment, as well as antiretroviral therapy in patients with AIDS, improve outcomes in immunosuppressed individuals.

Complications

Toxoplasmosis can cause severe life-threatening complications in immunosuppressed individuals manifesting as toxoplasmic encephalitis or extracerebral toxoplasmosis. Initiation of treatment can be complicated by immune reconstitution inflammatory syndrome (IRIS), resulting in a paradoxical worsening of symptoms. Treatment involves continuing anti-infective therapy, antiretroviral therapy, and starting steroids (or increasing dose if patients are already on steroids).

Deterrence and Patient Education

Infection with toxoplasma has been shown to be upwards of 60% in some parts of the world, and although primary infections can be self-limiting, there is a risk for more severe disease with reactivation of latent infection. Patients can reduce their risk of being infected by:

  • Cooking food to safe temperatures or freezing meats for several days at sub-zero temperatures prior to cooking
  • Thoroughly washing or peeling all fruits and vegetables.
  • Thoroughly washing surfaces that have come in contact with raw meat, poultry, seafood, and unwashed fruits or vegetables
  • Avoiding unpasteurized goat's milk
  • Wearing gloves and performing appropriate hand hygiene after contact with litter boxes and after contact with any sand or soil that may have been in contact with cat feces.

Enhancing Healthcare Team Outcomes

An interprofessional team approach in evaluating patients for toxoplasmosis can aid in early diagnosis and treatment. Given the high incidence of worldwide infection, efforts to reduce primary infection can help prevent individuals from being at risk of developing severe disease during their lifetime. Additionally, increased awareness and education regarding the use of prophylaxis therapy can help reduce the incidence of reactivation of latent infection.


References

[1] Tenter AM,Heckeroth AR,Weiss LM, Toxoplasma gondii: from animals to humans. International journal for parasitology. 2000 Nov     [PubMed PMID: 11113252]
[2] Jones JL,Kruszon-Moran D,Sanders-Lewis K,Wilson M, Toxoplasma gondii infection in the United States, 1999 2004, decline from the prior decade. The American journal of tropical medicine and hygiene. 2007 Sep     [PubMed PMID: 17827351]
[3] Stelzer S,Basso W,Benavides Silván J,Ortega-Mora LM,Maksimov P,Gethmann J,Conraths FJ,Schares G, {i}Toxoplasma gondii{/i} infection and toxoplasmosis in farm animals: Risk factors and economic impact. Food and waterborne parasitology. 2019 Jun;     [PubMed PMID: 32095611]
[4] Halonen SK,Weiss LM, Toxoplasmosis. Handbook of clinical neurology. 2013;     [PubMed PMID: 23829904]
[5] De Luca G,Di Lisio C,Lattanzio G,D'Antuono T,Liberatore M,Aiello FB, First case report of M1 macrophage polarization in an untreated symptomatic patient with toxoplasmosis. BMC infectious diseases. 2018 Mar 27;     [PubMed PMID: 29580227]
[6] Chimelli L, A morphological approach to the diagnosis of protozoal infections of the central nervous system. Pathology research international. 2011     [PubMed PMID: 21785681]
[7] Butler NJ,Furtado JM,Winthrop KL,Smith JR, Ocular toxoplasmosis II: clinical features, pathology and management. Clinical     [PubMed PMID: 22712598]
[8]     [PubMed PMID: 3326123]
[9] Vidal JE, HIV-Related Cerebral Toxoplasmosis Revisited: Current Concepts and Controversies of an Old Disease. Journal of the International Association of Providers of AIDS Care. 2019 Jan-Dec     [PubMed PMID: 31429353]
[10] Zoubi MA,Zulfiqar B,Kulkarni M, Cerebral toxoplasmosis requiring urgent brain biopsy. IDCases. 2017;     [PubMed PMID: 28702359]
[11] Holland GN,Lewis KG, An update on current practices in the management of ocular toxoplasmosis. American journal of ophthalmology. 2002 Jul;     [PubMed PMID: 12095816]
[12] Ayoade F,Joel Chandranesan AS, HIV-1 Associated Opportunistic Infections, Toxoplasmosis 2020 Jan;     [PubMed PMID: 28722907]