HIV-1–Associated Toxoplasmosis

Etiology

The causative agent is Toxoplasma gondii, an exclusively intracellular, coccidian protozoan parasite with worldwide distribution. Transmission occurs following ingestion of infectious oocysts from contaminated meat, food, or water. Infectious oocysts are abundant in damp, shaded soil and cat litter contaminated with feline feces. The tissues of pigs, lambs, goats, deer, and bears can become infected when these animals consume vegetation, water, or soil contaminated with cat-shed oocysts. Humans then acquire infection primarily through 2 routes: eating undercooked meat from infected intermediate hosts or directly ingesting oocysts from environmental contamination. Felines are the only animals in which T gondii can complete its reproductive cycle.

The T gondii parasite can exist as a sporulated oocyst, an unsporulated oocyst, or an intracellular tissue cyst. The sporulated oocyst is the infectious form for humans and is found in the soil. Unsporulated oocysts are released into the environment, mainly into soil through cat feces. After release, oocysts sporulate outside the cat and become infectious. Sporulated oocysts can remain infectious in the soil for months. Once ingested, the oocysts migrate from the intestinal epithelium to tissues and can spread to all organs and systems in the body. In tissues, the parasite develops into intracellular tissue cysts. Tissue cysts are usually slow-growing and dormant bradyzoites for years in immunocompetent hosts, whereas immunosuppression can cause cyst reactivation, rapid division, and active disease due to tachyzoites.[7] Latent infection can reactivate because of progressive loss of cellular immunity in patients with advanced HIV infection, after solid organ or stem cell transplant, with prolonged corticosteroid use, with monoclonal antibody therapy, or during chemotherapy.[7][8][9][10]

Epidemiology

According to a systematic review of observational studies conducted over decades that summarized the prevalence of Toxoplasma gondii seropositivity among people with HIV globally, 35.8% of people living with HIV had latent infection.[11] The highest seroprevalence estimates among people living with HIV were reported in resource-limited countries (54.7%) compared with high-income countries (26.3%). The incidence of symptomatic toxoplasmosis in people living with HIV continues to decline in areas with widespread antiretroviral therapy use, although cases still occur, particularly in individuals with advanced immunosuppression or delayed HIV diagnosis. Results from a recent Asia-Pacific cohort study showed that most cases occurred in individuals not receiving antiretroviral therapy, especially those with CD4 counts of 200 cells/µL or fewer, and that injection drug use and hepatitis B coinfection were additional risk factors.[4]

The prevalence of toxoplasmosis across all patient types, including immunocompromised and immunocompetent individuals, is much lower in high-income regions, such as Europe and North America, than in South America and Africa, except in Australia, which has the highest prevalence (54%).[12] The National Health and Nutrition Examination Survey reported that overall Toxoplasma seroprevalence in the US population from 2011 to 2014 was about 11%, with higher rates in certain subgroups and geographic regions.[13][14]

Although cats and related felines have traditionally been associated with toxoplasmosis, infection prevalence is not related to cat ownership. In patients with HIV and Toxoplasma seropositivity who have a CD4 count less than 100 cells/µL and are not receiving appropriate prophylaxis, the probability of developing reactivated toxoplasmosis is as high as 30%. Apart from oral transmission, toxoplasmosis can also be transmitted transplacentally from a pregnant patient to the fetus or through the transplant of an infected organ.

Pathophysiology

After a host ingests the infective forms, Toxoplasma gondii invades the intestinal epithelium and disseminates throughout the body. In tissues, most often the brain but potentially any tissue, the organisms encyst and remain dormant until immunity wanes. The dormant forms are called bradyzoites, whereas the actively replicating forms are called tachyzoites. Primary toxoplasmosis is often subclinical but may rarely present symptomatically in a seronegative immunocompromised person who has been recently exposed to the infective forms. In this scenario, IgM against Toxoplasma often yields a positive result, whereas IgG level results are negative, unlike most reactivation cases, in which IgG is the only serologic test result that is positive. As previously outlined, in most situations, clinical toxoplasmosis in patients with HIV is due to the reactivation of latent infection when immunity wanes.[15][16][17]

Toxoplasmosis can cause disease in any organ or organ system. In immunocompetent individuals, the most common presentation is Toxoplasma lymphadenitis. Other nonspecific manifestations include fever, malaise, arthralgia, myalgia, and sore throat resembling mononucleosis. Rarely, fatal toxoplasmosis with myocarditis, pneumonitis, and CNS manifestations has been reported in immunocompetent patients, possibly due to virulent strains.

Histopathology

The histology usually reveals diffuse encephalitis, cyst-containing lesions, microglial nodules, and lymphocytic vasculitis.

History and Physical

Cerebral toxoplasmosis (toxoplasmic encephalitis), usually with 1 or more ring-enhancing brain lesions, is the typical presentation in patients with HIV. Among patients with HIV, the most common presentation is focal encephalitis, which is characterized by headache, focal neurologic deficits, confusion, seizures, and reduced consciousness.[18] Symptoms are often subacute, ranging from a few days to a month. Fever may be present, but is usually absent. Findings from studies suggested that a chronic Toxoplasma infection may not be completely asymptomatic, and behavioral changes and neuropsychiatric disorders may occur in some patients. Mental status changes may range from a dull affect to stupor and coma, often secondary to global encephalitis or increased intracranial pressure. Conversely, the latent or dormant phase is usually asymptomatic.

Although uncommon, other manifestations such as pulmonary toxoplasmosis, chorioretinitis, hepatitis, and myocarditis have been reported. Involvement of the spinal cord leading to sensory and motor weakness with bladder and bowel involvement has also been reported. Pulmonary toxoplasmosis can often be mistaken for other atypical forms of pneumonia. Pulmonary toxoplasmosis may resemble pneumocystis pneumonia or be confused with pulmonary infection secondary to cytomegalovirus, Mycobacterium tuberculosis, Histoplasma capsulatum, Cryptococcus spp, and Coccidioides spp. Mortality from pulmonary toxoplasmosis remains high despite appropriate therapy. Diagnosis is made through bronchoalveolar lavage polymerase chain reaction testing for T gondii. Rarely, toxoplasmosis may present as disseminated disease.

Evaluation

No routine laboratory findings are specific to toxoplasmosis. However, lactate dehydrogenase levels can be markedly increased in patients with disseminated toxoplasmosis and pulmonary disease.[2][19][20] A presumptive diagnosis of cerebral toxoplasmosis in a patient with HIV can be made when the following criteria are present:

• CD4 count of fewer than 100 cells/µL without effective prophylaxis
• A compatible clinical syndrome (as described above in  the History and Physical section)
• A positive T gondii IgG antibody result
• Anti-Toxoplasma IgM antibodies are usually absent except rarely in cases of primary infection. Quantitative IgG antibody titers are not helpful in diagnosis.
• MRI brain imaging with contrast demonstrates typical radiographic findings, most commonly 1 or more ring-enhancing lesions with or without surrounding edema (see Image. Cerebral Toxoplasmosis).

If the above criteria are present, the probability of cerebral toxoplasmosis is at least 90%. However, clinicians should recognize that positive serologic test results do not confirm the diagnosis, and negative serologic test results imply that cerebral toxoplasmosis is unlikely, though not impossible. The ring-enhancing brain lesions on brain MRI findings may be multiple (67%) or single (33%), with a predilection for involvement of the basal ganglia, corticomedullary junction, or brain white matter. (see Image. Cerebral Toxoplasmosis).

A more definitive diagnosis can be made by obtaining a lumbar puncture if it is safe to perform. Cerebrospinal fluid analysis often shows mononuclear pleocytosis, elevated protein levels, and, sometimes, reduced CSF glucose levels.[21] Polymerase chain reaction testing for T gondii in CSF is 100% specific but only 44% to 65% sensitive. Therefore, positive CSF polymerase chain reaction results establish the diagnosis of cerebral toxoplasmosis, but negative results do not rule it out.

More recently, the enzyme-linked immunosorbent assay for detecting IgG avidity has been introduced. IgG avidity, which reflects the antibody's affinity for the antigen, typically shows low levels in acute infection but high levels in chronic or long-standing infection. IgG avidity testing is especially useful for distinguishing recent from chronic Toxoplasma infections in pregnant women who may transmit the infection vertically to their offspring. A combination of maternal IgG, IgM, and IgG avidity tests helps minimize false-positive results, especially when positive IgM results persist for a long time, as is often seen in toxoplasmosis. Vertical transmission risk is increased with recent infection or infection acquired in the first or second trimester of pregnancy compared with chronic infection acquired before pregnancy.[22][23]

A brain biopsy can be obtained when the diagnosis is in doubt, and alternative diagnoses are considered. Findings in cerebral toxoplasmosis may show necrotic abscesses with blood vessel thrombosis and necrosis. Cysts containing bradyzoites may often be found coexisting with numerous active tachyzoites. In most cases, a brain biopsy is not required for diagnosis.

Although advanced molecular diagnostics, such as real-time isothermal amplification and next-generation sequencing, are being explored, the standard of care remains a combination of clinical presentation, serology, and neuroimaging for presumptive diagnosis. Newer diagnostic modalities, however, are not yet widely adopted in routine clinical practice.[24] Most commonly, people living with HIV and suspected toxoplasmic encephalitis are treated empirically, without a definitive diagnosis (such as a brain biopsy). Because patients often have a good clinical response to therapy, histologic diagnosis is typically not required.

Treatment / Management

The treatment of toxoplasmosis in patients with HIV includes:

• Antimicrobial therapy directed against T gondii
• Antiretroviral therapy for immune recovery

Initial-phase therapy is followed by secondary prophylaxis or maintenance therapy, which continues until CD4-positive T-lymphocyte counts exceed 200 cells/µL for more than 6 months. The preferred drugs used in the initial phase of toxoplasmosis are pyrimethamine plus sulfadiazine plus leucovorin or trimethoprim-sulfamethoxazole. In patients with sulfonamide allergy, treatment options include pyrimethamine plus clindamycin plus leucovorin or atovaquone alone. Desensitization should be attempted when sulfonamide-containing therapy is clinically indicated. Atovaquone can be used alone or combined with either sulfadiazine or pyrimethamine. Leucovorin should always be included whenever pyrimethamine is used because pyrimethamine is a dihydrofolate reductase inhibitor, and leucovorin, or folinic acid, can reduce hematopoietic adverse effects. The initial phase of treatment should be given for 6 weeks after the resolution of signs and symptoms before the maintenance phase begins. In addition to awaiting immune recovery, secondary prophylaxis provides continuous therapy against dormant cystic forms, which may rupture and reinitiate the infectious process at any time. Maintenance therapy, preferably either double-strength trimethoprim-sulfamethoxazole twice daily or pyrimethamine plus sulfadiazine plus leucovorin, is necessary to prevent relapses.[HIV.gov. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV] 

In patients with sulfonamide allergy, desensitization should be initiated; in the meantime, atovaquone therapy, with or without pyrimethamine, should be started. For pregnant patients who acquire primary infection during pregnancy, spiramycin is recommended during the first 14 weeks of gestation to reduce fetal transmission because the drug is concentrated in the placenta and is nonteratogenic. For primary maternal infections acquired beyond 14 weeks or when fetal transmission is confirmed, treatment remains the same as in the nonpregnant population, with pyrimethamine plus sulfadiazine and leucovorin. Pyrimethamine and sulfadiazine are avoided in the first trimester due to teratogenicity.

Most clinicians use corticosteroids when edema is present, but study results have shown their use to be neither beneficial nor harmful. Adjunctive corticosteroids should be administered only to treat mass effect associated with focal brain lesions or related edema, or to control clinically significant immune reconstitution inflammatory syndrome symptoms, in conjunction with antiretroviral therapy and anti-Toxoplasma therapy. Corticosteroids should be discontinued when clinically possible to avoid further immunosuppression. For patients in whom the diagnosis of toxoplasmic encephalitis is presumptive based on clinical response, the clinical team should recognize that central nervous system lymphoma may also respond to corticosteroids.

The treatment course is often dramatic, with half of patients showing neurologic improvement by day 3 and, in most cases, by day 7 after treatment initiation. When patients have no significant improvement or have worsening symptoms by days 10 to 14 of therapy, repeat imaging and possibly a brain biopsy should be considered. Persistent neurologic sequelae may remain in 37% of survivors, and the death rate at 1 year varies from 10% to 60%. Therapies that target latent cysts and have improved safety profiles remain needed, but no new agents have been adopted into the standard of care, according to results from a 2023 study.[24] Additionally, clinicians should be aware that the initiation of antiretroviral therapy or effective antiretroviral therapy can result in immune reconstitution inflammatory syndrome in patients with central nervous system toxoplasmosis.

Differential Diagnosis

The differential diagnoses for HIV-1–associated toxoplasmosis include the following:

• CNS lymphoma: CNS lymphoma can be radiographically indistinguishable from CNS toxoplasmosis on brain MRI and CT. Lymphoma should be considered next in the differential diagnosis when imaging findings are not characteristic of toxoplasmic encephalitis.
• CNS tuberculosis
• CNS cryptococcosis (cryptococcoma)
• CNS aspergillosis
• Progressive multifocal leukoencephalopathy caused by the JC virus
• Pyogenic bacterial brain abscess
• CNS metastatic cancer brain lesions

Complications

Complications of HIV-1–associated toxoplasmosis include the following:

• Changes in personality
• Seizures
• Cranial nerve palsy
• Hemiparesis
• Hemianopia
• Ataxia
• Aphasia