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