Infectious Disease and Microbiology – Toxoplasmosis

Toxoplasmosis is an infection caused by the intracellular protozoan Toxoplasma gondii. Infection is usually asymptomatic in immunocompetent people, but severe disease can occur in immunocompromised patients and in fetuses infected transplacentally during pregnancy. Symptomatic disease ranges from a mild, self-limited mononucleosis-like illness to disseminated infection involving the central nervous system, eyes, lymph nodes, skeletal or cardiac muscle, lungs, and liver.

Epidemiology

The frequency of previous exposure to T. gondii varies greatly according to geography, age, dietary practices, and environmental conditions. Seroprevalence generally increases with age.

Among people with HIV, the greatest risk of clinically significant toxoplasmosis occurs when the CD4 T-cell count falls below 100 cells/mm³, especially in patients who are seropositive and are not receiving effective antiretroviral therapy or prophylaxis.

Congenital toxoplasmosis occurs when maternal infection is transmitted across the placenta. The probability of fetal transmission generally increases as pregnancy progresses, while infection acquired earlier in pregnancy tends to cause more severe fetal disease.

Women who were infected before pregnancy and have established immunity are generally at very low risk of transmitting infection during a subsequent pregnancy unless they become severely immunocompromised.

Risk factors

Important risk factors include eating raw or undercooked meat containing tissue cysts, consuming contaminated fruits or vegetables, and exposure to soil or material contaminated with cat feces.

Cats are the definitive hosts of T. gondii and excrete environmentally resistant oocysts in their feces.

Immunosuppression is a major risk factor for reactivation, particularly advanced HIV infection, hematologic malignancy, solid-organ or hematopoietic transplantation, prolonged high-dose corticosteroid use, and treatment with other immunosuppressive agents.

Seronegative transplant recipients who receive organs from seropositive donors may acquire primary toxoplasmosis from the transplanted organ.

Prevention

People with HIV should be tested for T. gondii IgG antibodies after HIV diagnosis to determine whether they are at risk of reactivation.

Seropositive patients with CD4 counts below 100 cells/mm³ generally require primary prophylaxis.

Trimethoprim-sulfamethoxazole (TMP-SMX) is the preferred preventive regimen and also provides protection against Pneumocystis jirovecii pneumonia.

Alternative prophylactic options include combinations containing dapsone plus pyrimethamine and leucovorin, or atovaquone in selected patients.

Primary prophylaxis can generally be discontinued after sustained immune recovery with effective antiretroviral therapy.

High-risk transplant recipients may also receive TMP-SMX prophylaxis.

Pregnant patients who are seronegative should avoid raw or undercooked meat and unpasteurized products, wash fruits and vegetables thoroughly, wash their hands after handling raw meat or soil, and use gloves during gardening.

Cat litter should ideally be changed by another person during pregnancy. If this is not possible, gloves and careful hand hygiene should be used.

Pathophysiology

T. gondii has both sexual and asexual phases in its life cycle.

The sexual phase occurs in cats, where oocysts are produced in the intestinal tract and subsequently excreted in feces.

After oocysts sporulate in the environment, they become infectious and may remain viable for prolonged periods.

Humans and other intermediate hosts acquire infection by ingesting sporulated oocysts or tissue cysts.

After ingestion, parasites transform into rapidly replicating tachyzoites, which disseminate through the body and can infect numerous organs.

As host immunity develops, organisms persist in tissues as slowly replicating bradyzoites contained within tissue cysts, particularly in the brain, retina, skeletal muscle, and myocardium.

When cellular immunity becomes profoundly impaired, dormant tissue cysts may reactivate and produce severe disease.

Etiology

Toxoplasma gondii is an obligate intracellular protozoan.

Cats are the definitive hosts, while humans and many other mammals and birds serve as intermediate hosts.

Human infection commonly occurs through ingestion of undercooked meat containing tissue cysts, ingestion of environmentally contaminated food or water, transplacental transmission, or less commonly transplantation or transfusion.

Toxoplasmosis in immunocompetent patients

Approximately 80–90% of newly infected immunocompetent people are asymptomatic.

When symptoms occur, the most common presentation is lymphadenopathy, especially involving the cervical lymph nodes.

Patients may also experience fever, malaise, myalgias, arthralgias, sore throat, night sweats, headache, or a maculopapular rash.

The illness usually resembles infectious mononucleosis and is generally self-limited.

Rare manifestations include myocarditis, pericarditis, polymyositis, hepatitis, encephalitis, or other organ involvement.

Ocular toxoplasmosis

Toxoplasmosis is an important cause of chorioretinitis.

Many cases of ocular disease represent reactivation of congenital infection later in childhood or adulthood.

Patients may present with blurred vision, scotomas, ocular pain, photophobia, or excessive tearing.

Ophthalmologic examination typically shows yellow-white retinal lesions with surrounding inflammation, which may later develop sharply defined borders and areas of pigmentation or scarring.

Recurrences are relatively common and may progressively impair vision.

Toxoplasmosis in immunocompromised patients

In patients with advanced immunosuppression, toxoplasmosis most commonly involves the central nervous system.

CNS disease usually results from reactivation of latent infection rather than newly acquired disease.

Symptoms typically develop over days to weeks and include headache, fever, confusion, seizures, focal weakness or numbness, speech difficulty, imbalance, visual-field defects, and altered mental status.

Patients may also develop meningismus or cranial nerve abnormalities.

Extracerebral disease is less common but may involve the lungs, eyes, heart, gastrointestinal tract, liver, skin, or multiple organs simultaneously.

Pulmonary toxoplasmosis

Toxoplasmic pneumonitis may cause fever, progressive dyspnea, dry cough, and hypoxemia.

Pulmonary disease can resemble Pneumocystis jirovecii pneumonia, bacterial pneumonia, or other opportunistic pulmonary infections.

Congenital toxoplasmosis

Congenital infection has a highly variable presentation.

Some infected infants are asymptomatic at birth but develop complications months or years later.

Premature infants are more likely to present with severe neurologic or ocular disease, whereas full-term infants may initially have milder findings such as hepatosplenomegaly or lymphadenopathy.

Important manifestations include chorioretinitis, hydrocephalus, intracranial calcifications, seizures, developmental impairment, and hearing or visual abnormalities.

Physical examination

Patients with CNS toxoplasmosis may demonstrate focal motor or sensory deficits, cranial nerve abnormalities, visual-field defects, cerebellar signs, altered mental status, or meningismus.

In immunocompetent patients, lymph nodes are usually discrete, non-tender, non-suppurative, and less than approximately 3 cm in diameter.

Hepatomegaly may occasionally occur.

Patients with ocular disease require a detailed ophthalmologic examination because retinal lesions may be multiple and vision-threatening.

Diagnosis

Diagnosis is based on the combination of clinical presentation, immune status, serologic findings, and imaging, with direct demonstration of the organism in tissue providing definitive confirmation.

Serology

T. gondii-specific IgG and IgM antibodies are commonly used in the initial evaluation.

IgG generally indicates previous exposure, while IgM may suggest recent infection, although interpretation can be complicated by prolonged persistence or false-positive results.

In immunocompromised patients, antibody responses may be weak or absent, so negative serology does not completely exclude disease.

For an HIV-positive patient with typical brain lesions, however, a negative IgG makes reactivated toxoplasmosis substantially less likely.

PCR and direct detection

PCR may detect T. gondii DNA in CSF, amniotic fluid, blood, bronchoalveolar lavage fluid, or tissue specimens.

PCR can be particularly useful in congenital infection and selected immunocompromised patients, although sensitivity varies with specimen type and disease burden.

Tachyzoites may occasionally be identified directly in body fluids or tissues using cytologic stains or immunofluorescence.

Cerebrospinal fluid

CSF findings in CNS toxoplasmosis are usually nonspecific.

Patients may have mild lymphocytic pleocytosis and elevated protein, but CSF can also be nearly normal.

Neuroimaging

Brain MRI is more sensitive than CT and is preferred when CNS toxoplasmosis is suspected.

Typical findings are multiple ring-enhancing lesions surrounded by edema, commonly involving the basal ganglia, thalamus, corticomedullary junction, or other deep structures.

Although multiple lesions are characteristic, a solitary lesion can occur.

MRI findings must be interpreted in the clinical context because similar abnormalities may occur with primary CNS lymphoma, bacterial abscess, tuberculosis, fungal infection, or other opportunistic diseases.

Diagnosis of congenital disease

Prenatal diagnosis may use PCR of amniotic fluid, together with maternal serologic testing and fetal ultrasonography.

Fetal imaging may demonstrate ventriculomegaly, intracranial calcifications, hydrocephalus, or other abnormalities in severe cases.

Newborn evaluation includes serology, neurologic examination, ophthalmologic assessment, and appropriate imaging.

Brain biopsy

In patients with advanced HIV and typical CNS lesions, empiric treatment is commonly started before brain biopsy.

Biopsy should be considered when lesions are atypical, the patient deteriorates rapidly, or there is no convincing clinical or radiographic improvement after an appropriate therapeutic trial.

Histopathology may demonstrate tachyzoites and tissue cysts.

Differential diagnosis

In immunocompetent patients with lymphadenopathy, the differential diagnosis includes Epstein-Barr virus infection, cytomegalovirus infection, acute HIV infection, lymphoma, and other causes of lymphadenopathy.

In immunocompromised patients with focal CNS lesions, important alternatives include primary CNS lymphoma, cryptococcosis, tuberculosis or nontuberculous mycobacterial disease, bacterial brain abscess, fungal infection, and progressive multifocal leukoencephalopathy.

Ocular disease must be differentiated from other infectious and inflammatory causes of retinitis and chorioretinitis.

Treatment

Most asymptomatic immunocompetent patients do not require specific antiparasitic therapy.

Treatment is indicated for severe or persistent disease, ocular involvement threatening vision, CNS disease, pulmonary or disseminated infection, congenital infection, and disease occurring in immunocompromised patients.

First-line therapy

Traditional first-line treatment for severe toxoplasmosis consists of pyrimethamine plus sulfadiazine plus leucovorin (folinic acid).

Pyrimethamine inhibits folate metabolism in the parasite but can also cause significant bone marrow toxicity.

For this reason, leucovorin must always be administered with pyrimethamine to reduce hematologic toxicity.

Acute treatment of CNS toxoplasmosis typically continues for at least six weeks, with longer therapy when disease is extensive or response is incomplete.

Alternative therapy

TMP-SMX is an effective alternative regimen and is commonly used in many clinical settings.

Other alternatives include pyrimethamine plus clindamycin with leucovorin, or selected regimens incorporating atovaquone.

Choice of therapy depends on disease severity, drug tolerance, allergies, interactions, pregnancy status, and immune function.

Empiric treatment of CNS disease

In a patient with advanced HIV infection, positive Toxoplasma IgG, and typical ring-enhancing brain lesions, an empiric therapeutic trial is reasonable.

Clinical improvement is often evident within approximately one to two weeks.

Failure to improve should prompt reconsideration of the diagnosis and often brain biopsy or additional diagnostic testing.

Treatment during pregnancy

Management of acute maternal toxoplasmosis depends on gestational age and whether fetal infection has been demonstrated.

Spiramycin has historically been used to reduce fetal transmission when maternal infection is diagnosed but fetal infection has not been confirmed.

When fetal infection is established, regimens containing pyrimethamine, sulfadiazine, and leucovorin may be used later in pregnancy under specialist supervision.

Because treatment recommendations in pregnancy are highly specialized, management should involve maternal-fetal medicine and infectious-disease specialists.

Congenital toxoplasmosis

Infants with congenital toxoplasmosis require prolonged antiparasitic therapy, generally using combinations of pyrimethamine, sulfadiazine, and leucovorin.

Close ophthalmologic, neurologic, auditory, developmental, and laboratory follow-up is essential.

Corticosteroids

Corticosteroids are not routinely required.

They may be considered in selected patients with severe CNS mass effect or impending herniation, or in ocular toxoplasmosis with vision-threatening inflammation.

Steroids should only be used together with appropriate antiparasitic therapy because immunosuppression without treatment can worsen infection.

Secondary prophylaxis

Patients with HIV who recover from CNS toxoplasmosis require chronic maintenance therapy to prevent relapse.

Maintenance commonly uses lower-dose combinations of the same active agents used during induction.

Secondary prophylaxis can generally be discontinued after sustained immune reconstitution on antiretroviral therapy, typically when the CD4 count has remained above 200 cells/mm³ for an adequate period and the patient is clinically stable.

Monitoring

Patients receiving pyrimethamine require regular complete blood counts because bone marrow suppression can occur.

Sulfadiazine may cause rash, gastrointestinal intolerance, hepatitis, leukopenia, renal injury, or crystalluria, so renal function and other laboratory parameters should be monitored.

Patients with CNS disease should undergo repeated neurologic examinations and follow-up imaging to document improvement.

Newborns with congenital disease require repeated ophthalmologic examinations because ocular lesions may emerge or recur long after birth.

Prognosis

Most immunocompetent patients recover completely without treatment.

Patients with HIV-associated CNS toxoplasmosis usually improve substantially when therapy is started promptly and immune function is restored with effective antiretroviral treatment.

A lack of improvement after approximately 7–14 days of appropriate therapy should prompt reconsideration of the diagnosis.

Congenital disease has a variable prognosis depending on the timing and severity of fetal infection.

Ocular toxoplasmosis may relapse and can produce cumulative retinal damage.

Complications

Ocular toxoplasmosis may cause permanent central vision loss, retinal scarring, strabismus, or nystagmus.

CNS disease can cause seizures, persistent focal neurologic deficits, altered cognition, cerebral edema, and death when untreated.

Congenital infection may result in chorioretinitis, hydrocephalus, intracranial calcification, developmental impairment, seizures, and long-term visual or neurologic disability.

Disseminated toxoplasmosis in severely immunocompromised patients may lead to respiratory failure, myocarditis, hepatitis, multiorgan failure, and death.

High-Yield Pattern

Advanced HIV + CD4 <100 + multiple ring-enhancing brain lesions → strongly consider cerebral toxoplasmosis

Basal ganglia lesions + positive Toxoplasma IgG + focal neurologic deficits → classic CNS toxoplasmosis pattern

First-line severe disease → pyrimethamine + sulfadiazine + leucovorin

Leucovorin must accompany pyrimethamine to reduce bone marrow toxicity

No improvement after 1–2 weeks of appropriate empiric CNS therapy → reconsider diagnosis and evaluate for brain biopsy

Pregnancy → risk of fetal transmission rises with gestational age, but earlier fetal infection is generally more severe

Prevention → thoroughly cook meat, wash produce, avoid contaminated soil or cat feces, and provide prophylaxis to high-risk immunocompromised patients