D27 Toxoplasmosis

Introduction

Toxoplasma gondii (T. gondii) is an obligate intracellular protozoan of worldwide distribution. It was discovered over 100 years ago and is now regarded as one of the most successful parasites in view of its ability to infect and replicate in almost all warm-blooded animals. Infection in immunocompetent human has generally been regarded as of little significance, since an effective cell-mediated immunity towards T. gondii could control but not eradicate the infection. Latent infection is characterised by the persistence of the parasite in the host’s tissue. A defect in cell-mediated immunity of the infected person puts one at risk of reactivation. The commonest clinical manifestation in HIV-infected patients is encephalitis.

The biology and immunology of toxoplasmosis has been extensively reviewed.[1] T. gondii exists in three functionally distinct forms: oocysts, tachyzoites and tissue cysts containing bradyzoites. Oocyst is the infective form of T. gondii and is shed by the definitive host, the cat. Tachyzoites are the invasive form of the organism found in acute infection or reactivation. They rapidly multiply, leading to cell rupture and invasion of nearby cells, or are transported to other parts of the body via the blood or lymphatic system. They transformed into tissue cysts under pressure of the inflammatory response. Tissue cyst is the dominant form of the parasite containing hundreds or thousands of bradyzoites. The commonest sites of cyst formation are the brain, skeletal and cardiac muscles. The host’s T-cell mediated response plays a significant role in suppressing the replication of parasites. In an immunocompromised host, for example an HIV patient with a severely disrupted T-cell response, bradyzoites are released from the cyst and transformed back into tachyzoites causing invasion in the body.

Human becomes infected after consumption of raw or undercooked meat that contains tissue cysts, or ingestion of water or food contaminated by oocysts that have sporulated, a process that takes at least 24 hours. The parasite can also be spread by vertical transmission or organ transplantation. Eating raw oysters, clams, or mussels has been reported as risk factors for acquisition of toxoplasma in the United States.[2] The disease is not transmitted through human-to-human contact.

Epidemiology of toxoplasmosis

Seroprevalence of T. gondii increases with age, varies by population group and with geographic location. Higher prevalence can be found in Europe and other tropical countries. The prevalence of T. gondii in a group of randomly selected inhabitants in Hong Kong was 9.8%.[3] There is no obvious difference in seroprevalence between HIV and non-HIV infected population. About one-third of HIV-infected patients have antibodies against T. gondii in the United States.[4]

Previous studies showed that toxoplasmic encephalitis (TE) would ultimately develop in 25-50% of patients with AIDS, especially for those with CD4 counts less than 100/μL. Most of the encephalitic cases have most likely resulted from reactivation of latent infection. However, with the introduction of potent antiretroviral therapy and primary prophylaxis, the risk of toxoplasmosis has declined significantly. Between 1985 and 2006, toxoplasmosis accounted for 1.5% of all HIV patients with World Health Organization Stage IV diseases in Hong Kong.[5]

Clinical manifestations

Toxoplasmosis in HIV-infected patients manifests primarily as encephalitis although a minority of them could also present as chorioretinitis, pneumonitis or disseminated infection. Clinical presentation of TE depends on the size, number and location of the brain lesions, and the immune status of the host. It is usually subacute in onset with focal neurologic signs frequently accompanied by fever (47%), confusion (52%) and headache (55%).[6] Cerebellar, subcortical or cortical lesions can be present in over 50% of infected cases, resulting in hemiparesis, ambulatory, gait or speech abnormalities. A significant proportion of encephalitic patients can also manifest with neuropsychiatric diseases including psychosis, dementia, anxiety and personality disorder.

The differential diagnoses of toxoplasmosis are:

• Lymphoma of the central nervous system (CNS)
• Progressive multifocal leukoencephalopathy (PML)
• Tuberculosis, including tuberculoma
• Focal CNS lesions caused by other infection including Cryptococcus neoformans, Aspergillus spp, Mycobacterium tuberculosis (M. tuberculosis), and Nocardia spp
• Cytomegalovirus or Herpes simplex encephalitis
• Bacterial brain abscess

Making a diagnosis

Diagnosis of TE is made by clinical, serologic, radiological, histological or molecular methods, or by a combination of these. Clinical signs of CNS toxoplasmosis are quite non-specific. However, an HIV-infected person with CD4 T-cell count less than 100/μL who presents with compatible focal CNS signs should alert clinician of the diagnosis.

Anti-T gondii IgG antibodies start to rise 1 to 2 weeks after acquisition of the infection and peak at 6 to 8 weeks. They decline gradually over the next 1 to 2 years but may persist for life in some cases. The majority of HIV-infected patients with TE have IgG antibodies.[6] However, measurement of IgG level could not differentiate between recently acquired and distant infection. Anti-T gondii IgM antibodies tend to appear earlier (within 1 week) and decline faster than IgG antibodies. The absence of IgM virtually excludes recent infection in immunocompetent patients. However, they can remain elevated for years and thus are not recommended for routine use. Quantitative antibody titres are not recommended for diagnosis.

Magnetic resonance imaging (MRI) is more sensitive than computed tomography (CT) scan in diagnosing encephalitic brain lesions for toxoplasmosis. Typical radiological findings comprise of bilateral, multiple, ring-enhancing lesions over basal ganglia and corticomedullary junctions of cerebral hemisphere. Surrounding oedema and mass effect are variably present. The most important differential diagnosis to consider for brain lesion in an AIDS patient is CNS lymphoma.[Chapter E31] Features that favour the diagnosis of T. gondii encephalitis over CNS lymphoma include: subcortical lesions, more than 3 lesions, absence of ependymal or leptomeningeal involvement, marked peri-lesional oedema, absence of hyperattenuation on nonenhanced CT scans or slender uniform ring-enhancing foci.[7] Increased uptake in newer imaging techniques like single-photo emission computed tomography (SPECT) or positron emission tomography (PET) can enhance the specificity in the detection of CNS lymphoma.

Brain biopsy showing tachyzoites or cyst provides a definitive diagnosis for TE. It is rarely performed nowadays since empirical therapy for cases with suspected toxoplasmosis can usually confirm the diagnosis. It should be considered in patients who fail to respond to anti-T gondii therapy or are suspected to have a diagnosis other than toxoplasmosis.

Cerebrospinal fluid and blood sample for toxoplasmic polymerase chain reaction (PCR) yields a diagnosis with variable sensitivity but a high specificity. A positive PCR in brain tissue does not necessarily indicate active infection. CSF can also be investigated by culture, cytology, cryptococcal antigen, PCR for M. tuberculosis, Epstein-Barr virus (EBV) and JC virus (JCV), especially in patients with suboptimal response to empirical toxoplasmosis treatment.

Treatment of toxoplasmosis

Since TE was the most common cause of focal CNS lesions in AIDS patients before the HAART era, empiric anti-T. gondii therapy used to be the standard approach in clinical management. With the falling incidence of TE, this empiric therapeutic approach may miss or delay the appropriate work-up and therefore management of other important conditions like CNS lymphoma.

Algorithm 27 illustrates the management approach to TE in HIV/AIDS in the local setting. In general, the presence of multiple brain lesions in an HIV patient with CD4 counts less than 100/μL and positive anti-T. gondii antibodies, who is not taking anti-T. gondii prophylaxis is highly predictive of TE.

Combination of pyrimethamine/sulfadiazine and folinic acid is considered the standard regimen for the treatment of TE.[Box 27.1][8] Sulfadiazine is not available in Hong Kong. Clindamycin can be used instead of sulfadiazine. Infected patient should be treated for at least 4-6 weeks after the resolution of all signs and symptoms. It is important to note that, as sulfonamides and pyrimethamine are myelotoxic, “folinic acid” instead of “folic acid” should be used since the latter could reverse the action of pyrimethamine. The efficacy of trimethoprim/sulfamethoxazole (co-trimoxazole) appears to be comparable to that of pyrimethamine/sulfadiazine in AIDS patients.[9] Short course of corticosteroid can be used in TE patient with significant cerebral oedema and elevated intracranial pressure. Prophylactic anticonvulsant is not recommended.

It has been reported that 51% of patients with TE had clinical response to anti-T. gondii therapy within the first 3 days, up to 91% by day 14.[10] Other investigations including brain biopsy should be considered if there is no improvement by 2 weeks or when there is deterioration by day 3. Over 90% of patients would have radiological response after 2 weeks of therapy. Monitoring CT/MRI brain every 4-6 weeks is suggested until there is complete resolution of the lesions.

Preventing toxoplasmosis in HIV infection

Prophylaxis

After acute treatment for TE in an AIDS patient, maintenance therapy (secondary prophylaxis) should follow since the current anti-T. gondii therapy cannot eradicate tissue cysts. Normally the same medications that have been used in the acute phase are given at half doses for secondary prophylaxis.[Box 27.1]

Primary prophylaxis should be considered in HIV patient with CD4 counts less than 100/μL. Use of co-trimoxazole for the prophylaxis of Pneumocystis pneumonia could provide protection against toxoplasmosis. Other alternatives include high dose dapsone alone or dapsone plus pyrimethamine. Both primary and secondary prophylaxis can be discontinued when the patient’s CD4 count has returned to more than 200/μL for at least 3 months.[11]

General preventive measures

HIV-infected persons should be tested for baseline IgG antibodies to Toxoplasma to detect latent infection with T. gondii. All HIV-infected persons should be assessed to explore sources of toxoplasmic infection and counselled on means of prevention:

• Avoid eating raw or undercooked meat, including undercooked lamb, beef, pork, or venison; and avoid raw shellfish including oysters, clams, and mussels
• Wash hands after contact with raw meat and after gardening or other contact with soil
• Wash fruits and vegetables well before eating them raw
• Avoid handling cats’ litter; use gloves and wash hands thoroughly after changing the litter box if one must do so
• Keep cats inside and not to adopt or handle stray cats
• Cats should be fed only canned or dried commercial food or well-cooked table food, not raw or undercooked meat

References