What is the overview of toxoplasmosis, particularly in immunocompromised adults, such as those with Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS)?

Toxoplasmosis Overview

Toxoplasmosis is a potentially life-threatening opportunistic infection caused by the intracellular protozoan parasite Toxoplasma gondii, which poses the greatest risk to immunocompromised patients—particularly those with HIV/AIDS—where it most commonly manifests as encephalitis and requires urgent recognition and treatment to prevent mortality. 1, 2, 3

Epidemiology and Transmission

General Population

• Toxoplasmosis occurs worldwide and remains asymptomatic in approximately 80% of immunocompetent individuals 4, 3
• Older children, adolescents, and adults typically acquire infection through consuming undercooked meat containing parasitic cysts or by ingesting sporulated oocysts from contaminated soil, food, or water 5
• The overall seroprevalence varies dramatically by geographic region and population, ranging from 3% to 97% in HIV-infected patients globally 6

Congenital Transmission

• The incidence of congenital toxoplasmosis in the United States is estimated at 1 per 1,000-12,000 live births, with substantial decline over the past 20 years 5
• In HIV-uninfected women with primary infection during pregnancy, the overall maternal-fetal transmission risk is 29% (95% CI: 25%-33%) 5
• Critical distinction: Transmission risk increases sharply with gestational age—from 2-6% in the first trimester to as high as 81% when infection occurs in the final weeks of pregnancy, though early infection causes more severe fetal disease 5
• In HIV-coinfected pregnant women with chronic toxoplasmosis, reactivation can occur with severe immunosuppression, resulting in perinatal transmission rates <4% 5
• HIV-infected pregnant women should undergo serologic testing for Toxoplasma, and all infants born to HIV-infected, Toxoplasma-seropositive mothers require evaluation for congenital infection 5

HIV/AIDS-Specific Epidemiology

• Among HIV-infected patients in eastern China, anti-Toxoplasma IgG seroprevalence was 9.7%, significantly higher than healthy controls (4.7%) 4
• Toxoplasmic encephalitis (TE) was historically the most common focal cerebral lesion in AIDS patients, occurring in approximately 50% of Toxoplasma-seropositive patients prior to HAART 6
• In HIV-infected children, CNS toxoplasmosis was reported as an AIDS-defining condition in <1% of pediatric AIDS cases even before HAART, with most cases representing congenital infection 5
• The advent of HAART has markedly decreased TE incidence, though it remains a significant cause of morbidity and mortality 6

Clinical Manifestations

Congenital Toxoplasmosis

• 70-90% of infected infants are asymptomatic at birth, but the majority develop late sequelae (retinitis, visual impairment, intellectual or neurologic impairment) with onset ranging from months to years 5, 7
• When symptomatic at birth, two presentations occur: generalized disease or predominantly neurologic disease 5
• Generalized disease features include maculopapular rash, generalized lymphadenopathy, hepatosplenomegaly, jaundice, and hematologic abnormalities (anemia, thrombocytopenia, neutropenia) 5
• Neurologic manifestations include hydrocephalus, intracerebral calcification, microcephaly, chorioretinitis, and seizures 5, 7

Acquired Toxoplasmosis in Immunocompetent Hosts

• Most often initially asymptomatic 5
• When symptomatic, presents with nonspecific findings: malaise, fever, sore throat, myalgia, cervical lymphadenopathy, and a mononucleosis-like syndrome with maculopapular rash and hepatosplenomegaly 5

Toxoplasmic Encephalitis in HIV/AIDS

• Focal neurological deficits are the most common presentation, though diffuse CNS disease can occur 2
• Fever, reduced alertness, and seizures are frequently observed 5, 2
• Toxoplasma encephalitis should be considered in all HIV-infected patients presenting with new neurologic findings, regardless of whether focal or diffuse 5
• The initial presentation can be variable and reflect diffuse CNS disease even when focal findings are more typical 5, 2

Other Manifestations in Immunocompromised Patients

• Less frequently observed presentations include systemic toxoplasmosis, pneumonitis, hepatitis, and cardiomyopathy/myocarditis 5, 1
• Isolated ocular toxoplasmosis is rare and usually occurs in association with CNS infection; neurologic examination is indicated for all patients with Toxoplasma chorioretinitis 5
• Ocular toxoplasmosis appears as white retinal lesions with minimal associated hemorrhage; visual loss may be the initial presentation 5

Diagnosis

Serologic Testing

• Serologic testing is the major diagnostic method, but interpretation of available assays is often confusing and difficult 5, 2
• Using specialized reference laboratories capable of performing serology, organism isolation, and PCR with assistance in result interpretation is recommended, especially for congenital toxoplasmosis 5
• Cases of Toxoplasma encephalitis have been reported in persons without Toxoplasma-specific IgG antibodies, so negative serology does not exclude the diagnosis 2

Congenital Toxoplasmosis Diagnosis

• Diagnosed by detecting Toxoplasma-specific IgM, IgA, or IgE in neonatal serum within the first 6 months of life, or persistence of specific IgG antibody beyond 12 months 5
• IgA may be more sensitive than IgM or IgE for detecting congenital infection 5
• Critical limitation: Approximately 20-30% of infants with congenital toxoplasmosis will not be identified in the neonatal period with IgA or IgM assays 5
• Complete neonatal evaluation must include Toxoplasma-specific antibody testing, ophthalmologic examination for chorioretinitis, neurologic examination, lumbar puncture for CSF analysis, and head imaging to evaluate for hydrocephalus or intracranial calcifications 7

Direct Detection Methods

• Additional diagnostic methods include isolation of the Toxoplasma parasite by mouse inoculation or tissue culture inoculation of CSF, urine, placental tissue, amniotic fluid, or infant blood 5
• Toxoplasma gondii DNA can be detected by PCR performed in reference laboratories on body fluids (white blood cells, CSF, amniotic fluid) or tissues 5
• Direct detection of the causative agent is needed in immunocompromised patients because serodiagnosis is not reliable due to altered immune response 3

Neuroimaging

• CT or MRI of the brain is essential for diagnosis of neurotoxoplasmosis 2
• CT typically shows multiple, bilateral, ring-enhancing lesions, especially in the basal ganglia and cerebral corticomedullary junction 2
• MRI is more sensitive than CT and will confirm basal ganglia lesions in the majority of patients 2

Treatment

Neurotoxoplasmosis Treatment

• Pyrimethamine (2 mg/kg/day for 3 days, followed by 1 mg/kg/day) plus sulfadiazine (25-50 mg/kg/dose four times daily) and leucovorin (10-25 mg/day) is the preferred treatment regimen 2
• Acute therapy should be continued for 6 weeks, assuming clinical and radiological improvement 2
• Leucovorin (folinic acid) must always be administered with pyrimethamine to minimize bone marrow suppression 2
• Complete blood count should be performed at least weekly while on daily pyrimethamine and at least monthly while on less frequent dosing 2
• For patients who cannot tolerate sulfa drugs, pyrimethamine plus clindamycin is an alternative, though only pyrimethamine plus sulfadiazine provides protection against PCP as well 5

Secondary Prophylaxis

• The combination of pyrimethamine plus sulfadiazine and leucovorin is highly effective for preventing recurrence 5
• Among HIV-infected children, lifelong suppression is indicated following treatment for toxoplasmosis to prevent recurrence 5
• The gold standard for both treatment of reactivation and secondary prophylaxis is the pyrimethamine-sulfadiazine combination 3

Prognosis

• If inadequately treated or left untreated, toxoplasmosis generally has a fatal prognosis in immunocompromised patients; therefore, treatment must be started as early and aggressively as possible 3

Prophylaxis Considerations

Primary Prophylaxis in HIV/AIDS

• TMP-SMZ, when administered for PCP prophylaxis, also provides prophylaxis against toxoplasmosis 5
• Atovaquone might also provide protection 5
• Co-trimoxazole can be used in primary prophylaxis for high-risk patients 3
• Chemoprophylaxis should be considered in HIV-infected patients with CD4 count <200 cells/mm³, particularly in resource-limited settings without access to HAART 6
• Toxoplasma screening programs are recommended for all newly diagnosed HIV-positive patients 6

Pregnant Women

• TMP-SMZ can be administered for prophylaxis as described for PCP 5
• Because of the low incidence of TE during pregnancy and possible teratogenicity concerns with pyrimethamine, chemoprophylaxis with pyrimethamine-containing regimens can reasonably be deferred until after pregnancy 5
• For prophylaxis against recurrent TE, most clinicians favor lifelong therapy for the mother given the high likelihood of prompt recurrence if therapy is stopped 5

Risk Factors

Behavioral and Environmental

• Major risk factors include contact with cats, consumption of raw vegetables and fruits, age, and CD4 counts 8
• HIV-infected persons should avoid contact with human and animal feces, wash hands after contact with feces or pets, and avoid sexual practices resulting in oral exposure to feces 5
• Avoid drinking water directly from lakes or rivers and be aware that recreational water sources may be contaminated 5
• Avoid contact with newborn/young pets with diarrhea, and avoid acquiring dogs or cats aged <6 months 5
• Avoid exposure to calves and lambs and premises where these animals are raised 5

Special Populations at Risk

Highest Risk Groups

• HIV-positive individuals and transplant recipients—particularly hematopoietic stem cell transplant and heart transplant recipients—are at highest risk for severe, life-threatening disease 3
• The disease can involve any organ but most often affects the central nervous system 3
• Toxoplasmosis in immunocompromised individuals can be life-threatening and requires aggressive management 8, 9