Toxoplasma gondii is a protozoan parasite that infects almost all species of animals, including humans. It causes the disease toxoplasmosis, which is generally asymptomatic and rarely lethal in healthy adults. Before the advent of the AIDS epidemic, T. gondii was not considered a pathogen of any consequence to humans. However, given the high numbers of asymptomatic infected individuals and the potentially fatal consequences of infection in immunocompromised patients, toxoplasmosis has become a serious concern for the medical community.
Below is the life cycle of the parasite from the Centers for Disease Control.
The life of T. gondii begins in the small intestine of the cat, where the organisms develop first to produce schizonts and gametocytes. Finally, oocysts are formed and these are passed in the cat’s feces. Each oocyst contains two sporocysts. Each sporocyst contains four sporozoites.
Trophozoites are found in the mesenteric lymph nodes and other organs of the cat. They are crescent-shaped. There are two forms. The quickly multiplying forms, tachyzoites, are responsible for the initial spread of infection and tissue destruction. The slower-developing bradyzoites are responsible for forming cysts.
T. gondii cyst, unstained
T. gondii sporulated cyst T. gondii unsporulated cyst
T. gondii sporulated cyst T. gondii unsporulated oocyst
differential interference contrast (DIC) differential interference contrast (DIC)
T. gondii sporulated and unsporulated oocysts
UV fluorescence microscopy (CDC 2007)
stained with Giemsa (CDC 2007)
Transmission to humans primarily occurs in one of two ways: 1) exposure to oocysts from direct contact with cat feces or ingestion of contaminated vegetables and 2) ingestion of tissue cysts from undercooked pork or lamb meat.
There are also a few less likely ways to get toxoplasmosis: 1) transplacental transmission from mother to fetus, 2) accidental inoculation of tachyzoites, 3) organ transplantation or blood transfusion.
Toxoplasma gondii is not actually a parasite of humans, but of cats, in which little disease is actually manifested. Cats and members of the feline family are the only definitive hosts for T. gondii and they are the main reservoirs.
T. gondii oocysts in a fecal flotation (CDC 2007)
Toxoplasma gondii is one of the world's most successful parasites, with up to one third of the world's population carrying the infection and approximately 40% of those living in the United States having been exposed at some point in their lives (Remington 2007).
Based on serologic evidence, the incidence of T. gondii infection varies depending on geography and population group. According to the third National Health and Nutritional Assessment Survey (NHANES III), between 1988 and 1994, 22.5% of adults across the United States were seropositive for antibodies against T. gondii. The rate of seroprevalence can be as high as 90% in Western Europe and tropical countries, where undercooked meat is commonly consumed (Subauste 2006).
While acute infection in immunocompetent individuals is usually asymptomatic, toxoplasmic encephalitis usually occurs in HIV-infected patients with CD4 T-cell counts below 100. Between Between 10% and 40% of HIV-infected patients in the United Sates have antibodies against T. gondii. Early studies indicated that 24-47% of T. gondii-seropositive AIDS patients ultimately developed toxoplasmic encephalitis. With the introduction of effective antiretroviral therapy (ART), however, the incidence in the United States of toxoplasmic encephalitis among patients diagnosed with AIDS declined from 2.1/100 person-years in 1992 to 0.7/100 person-years in 1997 (Subauste 2006).
Toxoplasmosis in non-immunocompromised patients:
The T. gondii parasite is approximately the size of a red blood cell. The form that causes acute disease can invade every cell of the mammalian host and form intracellular cysts, each of which contains thousands of parasites. It is estimated that approximately 15% of people in the United States have these cysts in the heart, skeletal muscle or nervous system tissues, but the majority of them are asymptomatic and will remain so for the rest of their lives so long as they are immunocompetent.
Toxoplasma infection in most adult humans is asymptomatic because of effective immunity, which consists of antibodies and T-cell factors acting intra- and extra-cellularly.
Toxoplasmosis in immunocompromised patients:
The three groups of immunocompromised patients most at risk for developing disease from T. gondii exposure or from reactivation of latent toxoplasmosis are:
1) the fetus of an infected pregnant women (infection passes transplacentally)
2) heart transplant patients (from exposure or from reactivation)
3) HIV patients (99.9% from reactivation).
When the patient is immunocompromised, immunity is not acquired quickly enough. This allows tachyzoites to multiply and destroy cells, produce lesions, and cause pneumonia, encephalitis and eventual death. Even when immunity is acquired, bradyzoites can develop into actively multiplying tachyzoites as soon as protective immunity fails. These tachyzoites usually parasitize cells in the brain, causing encephalitis.
Toxoplasmosis in AIDS patients:
The vast majority (over 99.9%) of AIDS patients who suffer from chronic toxoplasmosis are experiencing a relapse of a latent Toxoplasma infection. AIDS patients usually suffer from toxoplasmic encephalitis, but 50-70% of them also have non-localized involvement of the heart and lungs. It is unclear what specifically causes a relapse of chronic infection in immunocompromised patients, but it is generally believed that the lack of protective immunity makes the AIDS patient particularly susceptible to the progression of the disease to the chronic phase.
As a special note, in patients that are pregnant and HIV-positive, T. gondii, left untreated, can cause the baby to contract both HIV and toxoplasmic encephalitis.
Toxoplasmic encephalitis is the most common opportunistic central nervous system infection in AIDS patients. The lifetime risk of developing encephalitis caused by T. gondii in an immunocompromised patient is approximately 28%. Usually, necrotizing encephalitis results from the relapse of a latent infection through reactivation or rupture of tissue cysts in the brain.
In general, necrotizing encephalitis is prone to affect the corticomedullary junction, basal ganglia and thalamus areas. Occasionally, the encephalitis also affects the brain stem (Offiah et al. 2006).
The arrow points to an intense grey lesion, where there is toxoplasmic encephalitis.
Toxoplasmic encephalitis (Remington 2007)
T. gondii cyst in brain (CDC 2007)
More than a few patients have first sought medical attention for toxoplasmic encephalitis after suffering from partial or full motor seizures (Soto-Hernandez et al. 2006). Some patients may even suffer from Wernicke’s Aphasia due to partial status epilepticus. It is thought that cysts located in the language centers of the brain cause recurring seizures and aphasia (Ozkaya et al. 2006).
Acute Psychotic Episode
Some AIDS patients manifest toxoplasmic encephalitis through acute psychosis followed by rapid mental and somatic decline. This is almost always followed by certain death within a period of months.
Septic Shock and Rapid Death
In AIDS patients, acute disseminated and severe toxoplasmosis causes septic shock and rapid death. Due to suppressed immunity, there are more T. gondii cysts and tachyzoites in the body organs upon autopsy (Barbosa et al. 2007).
Ocular and Pulmonary Toxoplasmosis:
Frequently, patients with central nervous system toxoplasmosis will also have ocular toxoplasmosis, caused by activation of cysts deposited in or near the eye. The classic clinical presentation is retinal infection and associated inflammatory response, characterized by retinitis and uveitis (inflammation of the uveal tract of the eye, including iris and choroid) (Subauste 2006).
Severe, active retinochoroiditis
Central, healed retinochoroiditis
Peripheral retinochoroiditis (CDC 2007)
Most patients with pulmonary toxoplasmosis present with cough, dyspnea, and fever. Immunosuppressed patients are particularly susceptible to disseminated infections. Most pulmonary cases occur in patients with AIDS.
Dr. Remington’s Story
There was once a famous Stanford neurologist who was lecturing at a conference in France when he became inarticulate for the first time in his life. His partner immediately took him home and the neurologist was diagnosed with toxoplasmic encephalitis. The neurologist had been unaware of his HIV-seropositivity and his inability to speak as he normally could at the conference was his first sign that he was infected with T. gondii. He subsequently died.
Clinically, patients with toxoplasmic encephalitis will present with poor cognition, paralysis, seizures, decreased mental functioning, and headache. Most patients are unaware of HIV-seropositivity.
Physicians should test the patient’s HIV status and then perform serologic tests to detect T. gondii infection. T. gondii serology is particularly useful in diagnosis of infection in HIV-infected patients; between 97% and 100% of HIV-infected patients with toxoplasmic encephalitis have anti-T. gondii IgG antbodies (Subauste 2006). Thus, the absence of antibodies against T. gondii makes the diagnosis of toxoplasmosis unlikely in these patients.
When testing for specific antibodies, it is important to test for IgG and not IgM because IgM indicates an acute infection only because it is the first antibody formed against the antigen.
Formalin-fixed tachyzoites, stained by immunofluorescence (IFA): The fluorescence tells us this is a positive IgG reaction (CDC 2007)
Negative IFA for antibodies to T. gondii (CDC 2007)
Toxoplasmosis can be diagnosed by demonstration of tachyzoites in tissue biopsy or isolation of T. gondii from body fluids. Common methods include MRI, CT scan, brain biopsy, PCR, and cerebral spinal fluid test. MRI is more sensitive than CT in picking up lesions caused by toxoplasmic encephalitis (Offiah et al. 2006).
Often, toxoplasmic encephalitis is confused in the clinical setting with primary central nervous system lymphoma. The two pathologies may be indistinguishable on cross-sectional imaging (Offiah et al. 2006). Below, Image A is primary CNS lymphoma and Image B is toxoplasmic encephalitis.
Toxoplasmic encephalitis is highly responsive to antiparasitic chemotherapy (Offiah et al. 2006).
Combination therapy of pyrimethamine and sulfadiazine is highly effective in treating neurotoxoplasmosis, but not without consequences. Side effects include hematologic toxicity and cutaneous rash, causing up to 40% of patients to discontinue treatment. This puts them at a 30% risk of developing encephalitis (Remington 2007).
Secondary prophylaxis, or extended maintenance therapy, is needed to prevent relapses in patients with AIDS, as current antiparasitic regimens do not eradicate tissue cysts. Even with extended prophylactic treatment, death is still a distinct possibility (Leport et al. 1987)
Once patients with HIV are receiving successful antiretroviral therapy, maintenance therapy against toxoplasmic encephalitis can be discontinued safely. Patients will generally not relapse with the exception of a small minority (Bertschy et al. 2006). The general rule of thumb is this: if the patient’s CD4 T-cell count is below 200, then the patient should continue prophylaxis. If the patient’s CD4 count rises above 400 and remains stable for three to four months, then it is safe to discontinue prophylaxis. However, even with low CD4 counts, if the patient adheres to prophylaxis, his or her chance of developing encephalitis is about 1%. Before the advent of HAART, AIDS patients infected with T. gondii had a 30% chance of developing encephalitis and dying.