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, other food, or water. The oocysts are abundant in the soil, cat litter contaminated with feline feces or undercooked meat from an infected animal (especially felines). Felines are the only animals in which T. gondii can complete its reproductive cycle. After ingestion, the organisms encyst in nucleated cells and can lie dormant within the tissues for the life of the host (latent infection). In most scenarios, disease occurs following the reactivation of latent infection because of progressive loss of cellular immunity. This can occur in the setting of advanced HIV, following solid or stem cell transplant, prolonged steroids, use of monoclonal antibodies, or chemotherapy.[4][5]

Epidemiology

The incidence of toxoplasmosis infection depends on the seropositivity of Toxoplasma gondii in the population. In the United States, the seropositivity of T. gondii is approximately 10% of the adult population. Seropositivity is higher in Africa and Europe, where it can reach up to 80%, and toxoplasma encephalitis could be as high as 25% to 50% of susceptible hosts. The seropositivity in the HIV population mirrors that of the general population.[6][7]

Even though cats and related felines have traditionally been associated with toxoplasmosis, the prevalence of infection is not related to owning a cat. In HIV toxoplasma-seropositive patients with CD4 less than 100 who are not on appropriate prophylaxis, the probability of developing reactivated toxoplasmosis is as high as 30%. Apart from oral transmission, toxoplasmosis can also be transmitted via the placenta from mother to fetus or through transplantation of an infected organ.

Pathophysiology

After ingestion of the infective forms, the organism invades the intestinal epithelium and subsequently disseminates throughout the body. At the tissues, which often is the brain but can affect any tissue, they then encyst and lie dormant until immunity wanes. The dormant forms are called bradyzoites, while the actively replicating forms are called tachyzoites. Primary toxoplasmosis is often subclinical but could rarely present symptomatically in an immunocompromised seronegative person who became recently exposed to the infective forms. In this scenario, IgM to a toxoplasma is often positive, but IgG is not, unlike most reactivation cases, when IgG is the only positive serology test. As previously outlined, in most situations, clinical toxoplasmosis in the HIV patient is due to the reactivation of latent infection as immunity wanes.[8]

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 (see Image. Cerebral Toxoplasmosis). Symptoms are often subacute, ranging from a few days to a month. Common symptoms include a headache, confusion, and lethargy. Fever may be present but often absent. There is some suggestion that a chronic toxoplasma infection state may not be completely asymptomatic, and in some patients, behavioral changes and neuropsychiatric disorders are possible. Seizures and focal neurologic deficits are also common, occurring in up to 30% and 70% of patients, respectively. Mental status changes could range from dull affect to stupor and coma, often secondary to global encephalitis or increased intracranial pressure. On the other hand, the latent or dormant phase is often asymptomatic.

Extracerebral involvement is typically less common than CNS infection. These include pneumonitis and chorioretinitis, and less commonly, the gut, liver, heart, bladder, spinal cord, bone marrow, and testes. Rarely, toxoplasmosis may present as a disseminated disease.

Evaluation

There are no routine laboratory findings that are specific to toxoplasmosis. Lactate dehydrogenase (LDH) can be increased markedly in patients with disseminated toxoplasmosis and pulmonary disease.[2][9][10]

A presumptive diagnosis of cerebral toxoplasmosis in the HIV patient can be made as follows:

• CD4 count less than 100 cells/microliter without any effective prophylaxis
• A compatible clinical syndrome
• A positive T. gondii immunoglobulin (Ig) G antibody (Antitoxoplasma IgM antibodies are usually absent except rarely in cases of primary infection. Quantitative IgG antibody titers are not helpful in diagnosis.)
• Brain imaging (preferably MRI) that demonstrates a typical radiographic appearance

If the above criteria are present, there is at least a 90% probability the diagnosis is cerebral toxoplasmosis. However, it is important to note that a positive serology does not confirm the diagnosis, and a negative serology implies the diagnosis is not likely (though not impossible) to be cerebral toxoplasmosis.

Brain imaging often shows multiple (67%) or single (33%) ring-enhancing brain lesions often associated with edema. There is a predilection for involvement of the basal ganglia, corticomedullary junction, or brain white matter.

A more definitive diagnosis can be made by obtaining a lumbar puncture. Cerebrospinal fluid (CSF) analysis often shows mononuclear pleocytosis, elevated protein, and, sometimes, reduced CSF glucose. Polymerase chain reaction (PCR) testing for T. gondii in CSF is 100% specific but only 44% to 65% sensitive. This suggests a positive CSF PCR result establishes the diagnosis of cerebral toxoplasmosis, but a negative one does not rule it out.

When the diagnosis is in doubt, and alternative diagnoses are considered, a brain biopsy can be obtained. 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, brain biopsy is not required for diagnosis.

Treatment / Management

The treatment of toxoplasmosis in HIV-infected patients includes:

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

Pyrimethamine and sulfadiazine are most commonly employed in treatment. Both agents synergistically and sequentially block folic acid metabolism, which is necessary to develop the parasite. Folinic acid (leucovorin) is often added to replace folate stores, which are nonselectively depleted. Initial treatment is typically for 6 weeks.[11][12][13][12](A1)

Initial therapy is followed by secondary prophylaxis or maintenance therapy, which continues until CD4 plus T-lymphocyte counts are over 200 cells/microliters for over 3 months. 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, therefore, is necessary to prevent relapse.

In patients who are allergic to sulfonamides, treatment options include clindamycin, trimethoprim/sulfamethoxazole, pyrimethamine plus atovaquone plus folinic acid, pyrimethamine plus azithromycin plus folinic acid, and atovaquone alone (if unable to tolerate sulfur drugs or pyrimethamine). Spiramycin is the drug of choice in the first trimester of pregnancy, as pyrimethamine may be teratogenic.

Most clinicians often employ the use of steroids (when edema is present), but studies have shown its use to be neither beneficial nor harmful. The use of steroids in cerebral toxoplasmosis should probably be limited to impending brain herniation as the diagnosis may be clouded once the steroid is started before a definitive diagnosis is made.

The treatment course is often dramatic, with half the cases showing neurological improvement by day 3 and, in most cases, by day 7 of treatment commencement. If there is no significant improvement or worsening symptoms by days ten to 14 of therapy, repeat imaging and possibly brain biopsy should be considered. Persistent neurologic sequelae may remain in 37% of survivors, and the death rate at 1 year could vary from 10% to 60%.

An integral part of therapy is starting antiretroviral (ART) agents as soon as feasible, usually within 2 weeks of starting antitoxoplasma therapy. Immune reconstitution inflammatory syndrome (IRIS), which can present as a paradoxical worsening of symptoms as immunity recovers, is rarer with toxoplasmosis than mycobacterial and cryptococcal infections. Even though there are no studies about the optimal timing of ART in toxoplasmosis, early ART has clear benefits and should not necessarily be delayed beyond 2 weeks. [14][15](B3)

Differential Diagnosis

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

• CNS lymphoma
• CNS tuberculosis
• Cryptococcus
• Neurosyphilis
• Cardioembolic stroke
• Cytomegalovirus infection

Complications

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

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