ABSTRAK

Toxoplasma gondii menyebabkan penyakit di seluruh dunia yang disebut toksoplasmosis. Parasit ini telah menginfeksi hampir setengah dari populasi dunia, tetapi sebagian besar tidak menunjukkan gejala. Kucing diidentifikasi sebagai hospes definitif untuk parasit tersebut. Umumnya, parasit ini dapat masuk ke tubuh manusia dengan konsumsi ookista atau kista jaringan ditemukan dalam daging yang setengah matang. Infeksi ini akan parah pada pasien yang daya tahan tubuhnya yang rendah seperti terinfeksi HIV pasien atau wanita hamil. Seroprevalensi penyakit ini antara HIV adalah 3% sampai 97% di seluruh dunia. Penyakit ini diklasifikasikan ke dalam tahap akut dan kronis, dimana infeksi akut biasanya berhubungan dengan takizoit, suatu tahap dimana parasit ini aktif, sedangkan infeksi kronis yang disebabkan oleh kista jaringan. Faktor risiko infeksi toksoplasma pada pasien terinfeksi HIV termasuk usia, ras / etnis dan karakteristik demografis lainnya. Ada banyak cara untuk mendiagnosa toksoplasmosis pada pasien HIV seperti tes serologi, pencitraan, biopsi jaringan, dan polymerase chain reaction (PCR). Untuk menegakkan diagnosis pada pasien HIV yang diduga dengan toksoplasmosis, serologi tes dan studi pencitraan biasanya digunakan. Toksoplasmosis ensefalitis adalah infeksi oportunistik umum pada pasien AIDS. Berdasarkan penelitian, keterlibatan otak yang lebih umum dan masalah serius daripada keterlibatan luar otak. Gejala yang paling umum adalah sakit kepala, demam, kejang, hemiparesis, perubahan pada kesadaran dan koma. Ada juga toksoplasmosis occular (OT). Terapi lini pertama untuk toksoplasmosis akut pada pasien terinfeksi HIV adalah pirimetamin dan sulfadiazin. Kata kunci: Toxoplasma gondii, pasien HIV, toksoplasmosis ensefalitis, pirimetamin.

ABSTRACT

Toxoplasma gondii causing a worldwide disease called toxoplasmosis. These parasite were infecting almost half of worlds population, but most are asymptomatic. Cat were identified as the definitive host for these parasite. These parasite can enter human body by the ingestion of oocysts or tissue cysts found in undercooked meat, generally. This infection will severe in the immunocompromised patients such as HIV-infected patient or pregnant woman. The seroprevelance of these disease among HIV are 3% to 97% worldwide. These disease are classified into acute and chronic stages, where the acute infection usually associated with the tachyzoites, a rapid multiplying stages of the parasite, while the chronic infection are due to
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tissue cysts. The risk factors of Toxoplasma infection in HIV-infected patients include age, race/ethnicity and other demographic characteristics. There are many ways to diagnose the toxoplasmosis in HIV patients such as serology assays, imaging, tissue biopsy, and polymerase chain reaction (PCR). In other to make diagnose in HIV patient suspected with toxoplasmosis, serology test and imaging studies are usually used. Toxoplasmosis encephalitis is the common opportunistic infection in AIDS patients. Base on studies, cerebral involvement is more common and serious problems than an extra cerebral involvement. The most common symptoms are headache, fever, seizures, hemiparesis, alteration on consciousness and coma. There are also occular toxoplasmosis (OT). First line therapy for acute toxoplasmosis in HIV-infected patients is pyrimethamine and sulfadiazine.

Keywords: Toxoplasma gondii, HIV infected patient, toxoplasmosis encephalitis, pyrimethamine.

INTRODUCTION

Toxoplasmosis is a worldwide disease caused by the infection on T. gondii, which is a ubiquitous and intracellular protozoan parasite. About half of worlds population reported being infected but most are asymptomatic. The member of family Felidae, including cat were recognized as definitive host for this parasite, but can infecting human through the ingestion of the oocysts or tissue cysts found in undercooked meat [3,7]. Infected persons develop either mild flu-like illness characterised by fever, body aches, headaches and sore throat or no illness at all. People with a weakened immune system, such as those infected with HIV or pregnant women, may become seriously ill, and infection can occasionally be fatal [11].

EPIDEMIOLOGY OF TOXOPLASMOSIS IN HIV

The prevalence rates of toxoplasmosis among HIV are greatly varied from 3% to 97%. It is usually related to ethnicity, certain risk factors, and reactivation of toxoplasmosis. In United States, 15% to 29% of the general populations are seropositive for T. gondii infection while seroprevalence rates in Europe and tropical countries can reach 90%. Meanwhile in United States the prevalence of latent T. gondiii infection among persons with HIV infection does not differ from that in the general population. The usage of highly active anti-retroviral therapy (HAART) the incidence of central nervous system (CNS) toxoplasmosis has
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decreased. An estimation of 10% to 20% if HIV-infected patients in the United States ultimately will develop toxoplasmic encephalitis (TE). The risk for developing acute toxoplasmosis among HIV-infected adults was 18% in those who were compliant with prophylaxis versus 30% in those which were not compliant. Generally TE is a poor prognosis in AIDS patients [13]. In ASEAN countries, one of studies held in Malaysia shows that the seroprevalence of toxoplasmosis was 41.2% (95%CI: 35.5-46.9) in HIV/AIDS patients. The seroprevalence was significantly higher in the Malay (57.9%) than the Chinese (38.7%), followed by the Indian patients (29.6%) (p<0.05) [10].

PATHOGENESIS OF TOXOPLASMOSIS

T. gondii usually infects human via the oral, trans placental route, blood transfussion and organ transplantation. Consumption of raw or undercooked meat consisting viable cysts, water contaminated with oocytes from cat feces. And unwashed vegetables are the primary routes of oral transmission. It can transmit contaminated soil that may lead to hand-to-mouth infection. Human, carnivores, mammal and birds are the intermediate hosts for T. gondii, whereas cats are the definitive hosts. Infected cats spread disease when oocytes pass in their feces. When these oocytes pass into human they become tachyzoites, which undergo rapid replication. These tachyzoites then penetrate into nucleated cells and form vacuoles. After these cells, tachyzoites continue to spread through the body and infect other tissue as well as cause an inflammatory response [1,6,13].

Figure 1 Stages of T. gondii. Scale bar in (A) to (D)20 mm, in (E) to (G) 10 mm. (A) Tachyzoites in impression smear of lung. Note crescent-shaped individual tachyzoites (arrows), dividing tachyzoites (arrowheads) compared with size of host red blood cells and leukocytes; Giemsa stain. (B) Tissue cysts in section of muscle. The tissue cyst wall is very thin (arrow)

and encloses many tiny bradyzoites (arrowheads); haematoxylin and eosin stain. (C) Tissue cyst separated from host tissue by homogenization of infected brain. Note tissue cyst wall (arrow) and hundreds of bradyzoites (arrowheads); unstained. (D) Schizont (arrow) with several merozoites (arrowheads) separating from the main mass; impression smear of infected cat intestine, Giemsa stain. (E) A male gamete with two flagella (arrows); impression smear of infected cat intestine, Giemsa stain. (F) Unsporulated oocyst in faecal float of cat feces; unstained. Note double-layered oocyst wall (arrow) enclosing a central undivided mass. (G) Sporulated oocyst with a thin oocyst wall (large arrow), two sporocysts (arrowheads). Each sporocyst has four sporozoites (small arrow) which are not in complete focus; unstained [16].

Toxoplasmosis is classified into acute and chronic stages. For acute stages, the tachyzoites played important role while the chronic stages are more likely due to the tissue cysts. The tissue cysts amount will increase after 7 weeks of infection and stay in the host as viable parasite throughout the life of the host. During acute infection, the tachyzoites which is rapidly multiplying stages of parasite will attack all nucleated cell by actively penetrating through the host cell plasma membrane or by phagocytosis [7].

This will release the content of parasite which is the micronemes (responsible for target cell recognition and adhesion), the rhoptries that will release an enzyme to produce parasitophorous vacuole and lastly, the dense granule which secrete enzyme for vacuole maturation and will become metabolically active compartment. Host cell will be disrupted and tachyzoites will disseminate through the blood stream after repeated replication. This will lead to the host cell death, destroying adjacent cell and will lead to the formation of larger focal lesions [7].

However, with the response of host cell immune, the tachyzoites will undergo conversion into bradyzoites and then slowly to form tissue cysts, these tissue cysts will remain in the body of the host throughout the host life. For chronic infection, it was believed that reactivation happen due to the conversion of bradyzoites back into tachyzoites. During acute toxoplasmosis, lesion or tissue necrosis may found in many organs of the body, whereas for chronic infection, lesion more often occurs in muscle eye and brains [7].

In HIV-infected patients, expression of CD154 in response to T. gondii is impaired in cells. This impairment correlates with the decreased production of IL-12 and IFN-in response to T.gondii in HIV-infected patients. The cytoxic T-lymphocyte activity also impaired thus decreasing the host defense against T. gondii. As periodically the T. Gondii tissue cycts will be ruptured and releasing the bradyzoites. Immunity in immunocompetent
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hosts will prevents the released parasites from multiplying. However, decreased host defense leads to reactivation of chronic Toxoplasma infection in HIV-infected patients, especially T. gondii infection in HIV-infected patients, especially when the count decreases below 100cell/L [6,14]. Toxoplasmosis is often a reactivated rather than a new infection in AIDS patients [14].

Figure 2 Life cycle of T. Gondii [16]

RISK FACTORS

The risk factors of T. gondii infection in HIV-infected patients include age, race/ethnicity and other demographic characteristics. Based on study conducted in the United States, women aged 50 years old has higher risk to be infected with Toxoplasma than those who were younger [8]. The opposite result were found from a study conducted in Malaysia, which shows that the Toxoplasma seroprevalence is higher in HIV-infected younger age group than the older, although the difference was not statistically different. As the majority ethnic group in Malaysia, a study were conducted to prove the high rate of Toxoplasma in Malays than the other ethnic due to the Malays culture as they keeps cats as pets, which knows as definitive host for T.gondii. Based on these studies, demographic characteristic certainly make significant contributions to the epidemiological surveillance of toxoplasma infection in given
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population, such as HIV/AIDS patent. People that ate raw or under cooked meat, not properly washed vegetables will increase the risk of infection. People those who are not washing their hand after doing activities involving soil such as gardening also under high risk for infection [1].

CLINICAL IMPLICATIONS

Toxoplasmosis encephalitis is the common opportunistic infection in AIDS patients. Base on studies, cerebral involvement is more common and serious problems than an extra cerebral involvement. The most common symptoms are headache, fever, seizures, hemiparesis, alteration on consciousness and coma [1, 6, 14]. It is difficult to diagnose due to same manifestation with other neurological diseases. Every HIV-positive patient with neurological symptoms, the possibility of cerebral toxoplasmosis was considered although these symptoms may mimic those of other neurological diseases [1, 9]. A study conducted in India shows that HIV encephalopathy is the commonest cause of neurological manifestations in HIV-infected children and can present at any age. Delayed milestones are commonly seen in children ,5 years and focal signs and abnormal plantar reflexes are more common in older children [5].There are also reported an extra pyramidal symptoms such as Parkinsonism, hemichorea, and choreoathetosis. In country with high prevalence, TE should be considered to patients with movement disorder. Diabetes insipidus is uncommon but has been reported in relation with TE [1].

The prevalence of extra cerebral in patients with AIDS is far less common than the CNS toxoplasmosis, and the most common ECT founds is ocular toxoplasmosis. In developing countries, OT is most serious eye problem among HIV-infected patients; it is important and may be the first manifestation of life-threatening intracranial or disseminated T. gondii infections. OT tends to cause retinochoroidal scars with less retinal pigment and epithelial hyperplasia. Extra cerebral sites of involvement in such HIV-infected patients are ocular and pulmonary. The former present with chorioretinitis, vitritis and anterior uveitis while the latter present with fever and sepsis like syndrome with hypotension, disseminated intravascular coagulation, elevated lactic dehydrogenases and pulmonary infiltrates (similar to pneumocystis carinii pneumonia) [6]. The prognosis of toxoplasmosis in

immunosuppressed patients is grim, and the disease is usually fatal if untreated. Improvement may be seen if treatment is started early, but recrudescence is common [12]
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DIAGNOSTIC STUDIES

There are many ways to diagnose the toxoplasmosis in HIV patients such as serology assays, imaging, tissue biopsy, and polymerase chain reaction (PCR). In other to make diagnose in HIV patient suspected with toxoplasmosis, serology test and imaging studies are usually used [13].

Serology

The most commonly used serologic test is the detection of anti-toxoplasma antibodies, which are anti T. gondii IgG and IgM titres. The IgM antibodies appear sooner after infection than the IgG antibodies and disappear faster than IgG antibodies after recovery [16]. After primary infection, the serum IgG anti-toxoplasma titer will at highest point during the first two months and usually remains detectable for the rest of the patients life. Generally, to make a diagnosis of acute toxoplasmosis, serum assays are not suitable as these studies alone cannot distinguish active from latent infection. Reactivation of T. gondii infection can be indicated by an increase of the IgG level with the presence of clinical symptoms, but these are valid for patients with known baseline of anti-toxoplasma IgG levels. A negative serologic test for IgG makes the diagnosis of acute toxoplasmosis less likely, and other causes of focal neurologic deficits should be included in the differential diagnosis. Meanwhile, as patients with advanced HIV infection may become seronegative, acute toxoplasmosis was not definitively excluded if the IgG serology was negative, while in determining their serostatus, checking the patients medical record (if available) should be helpful. False negative results may occur in patients with recent infection or may occur due to insensitive assays [6,13].

IgM anti-toxoplasma antibody usually disappears within weeks to months after the primary infection but may remain elevated for more than 1 year. Therefore, elevated IgM levels do not always suggest recent infection. Elevated IgM levels does not always suggest recent infection, this is because IgM anti-toxoplasma antibodies usually disappears within weeks to months after primary infection but may elevated for more than 1 year. To making up diagnose of cerebral toxoplasmosis, IgM antibody test is generally not useful. This is due to the absent of anti-toxoplasma IgM antibodies in patients with reactivated disease where as the Toxoplasmic encephalitis in HIV-infected patients is most often due to reactivated disease [6, 13]. In pregnant patients, determining whether the infection is recent is important due to
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concerns for transplacental infection. It is challenging to interpret the IgM serology in a pregnant woman with HIV infection, if it is unknown whether the patient was seropositive for T. gondii prior to pregnancy. In this case, serologic testing should be repeated 3 weeks after initial serologic testing is performed. Positive and rising IgM levels can be interpreted as acute infection, recent infection, or a false-positive test result; however, positive IgM in the fetal blood is indicative of congenital infection [13,14]. Establishing recency of infection in pregnancy is of clinical importance with respect to medical intervention to minimize damage to the fetus, and there is not one test that can achieve this at the present time [16].

Imaging studies

In making Toxoplasma encephalitis diagnosis, CT scan approach was proved most helpful. A typical appearence of multiple, hypodence, ring-enhancing lesions in the cerebral hemisphere, particularly in the parietal area, are the majority findings in patients with TE [2]. There is one case studies recorded the finding of multiple ring enhancing intra-cerebral space occupying lesions in the left parietal, frontal, temporal lobes and in the right thalamic region of patients brain with CT scan [6]. Imaging studies usually show multiple lesions located in the region of the cerebral cortex, corticomedullary junction, or basal ganglia, although a single lesion may sometimes be present [9,13]. On MRI, lesions appear as low signal intensity on T1-weighted images and moderately hyperintense relative to the brain parenchyma on T2-weighted images. Enhancement may be subtle because of poor cellmediated immunity [9,13]. A hypodence lesion in the brain that revealed with a noncontrast CT scan can be mistaken for other types of focal brain lesions, but this can be corrected by repeating CT scan with contrast, which shows the typical ring-enhancing sign. As seen with CT with contrast, gadolinium-enhanced MRI usually demonstrates a ring-enhancing lesion with surrounding edema. MRI is the modality of choice for diagnosing and monitoring the response to treatment of toxoplasmosis because it more sensitive than CT for detecting multiple lesions. [13]. A studies conducted in India shows that abnormal MRI/CT findings included cerebral atrophy, infarcts and features of progressive multifocal

leucoencephalopathy (PML) in two cases and demyelination, hydrocephalus, features of HIV encephalopathy and toxoplasmosis in one cases each [5].

(3)

(4)

Figure 3 Magnetic resonance imaging of the brain showing ring enhancing lesions with surrounding edema in the bilateral temporoparietal lobes [13] Figure 4 CT Scan Image Showing Ring Enhancing Intra-cerebral Lesion in the Left Parietal Lobe of the Brain [6]

Cerebrospinal Fluid Analysis

Cerebrospinal fluid (CSF) analysis is rarely useful in the diagnosis of cerebral toxoplasmosis and is not performed routinely given the risk of increasing intracranial pressure with lumbar puncture. The case patient did not undergo lumbar puncture due to the presence of bilateral papilledema and the CT findings of bitemporoparietal lesions, which suggested a space occupying lesion and increased intracranial pressure. This diagnosis is performed if the diagnosis of toxoplasmosis is not clear in a patient with altered mental status or features if meningitis. CSF findings may include elevated white blood cell counts with mononuclear predominance [13].

TREATMENT AND PREVENTION First line therapy for acute toxoplasmosis in HIV-infected patients is pyrimethamine and sulfadiazine. As this combination leads to the sequential inhibition of enzymes in the folic acid synthesis pathway, leucovorin must be added to avoid hematologic complications. Acute infections should be treated for minimum of 3 weeks, but 6 weeks of therapy is preferred in patients who can tolerate it. Approximately 65% to 90% of patients respond to treatment with pyrimethamine, leucovorin and sulfadiazine.

Primary chemoprophylaxis with cotrimoxazole played an important role in preventing reactivation of toxoplasmosis in HIV-positive patients before the era of HAART. Mostly, the patient with TE responds well to anti-Toxoplasma agents as demonstrated by study in various settings. Patients intolerant to this combinations, it had been reported to be effective, including clindamycin and pyrimethamine [1]. In Indonesia, due to high seroprevalance in chicken and lamb, prevention can be done by avoiding the consumption of undercook meat. It is advisable to avoid eating sate ayam or half cooked lamb, and try to wash the fresh fruits or vegetable before consuming it. For pregnant mother, it is advisable to prevent direct contact with kitten or soil that contaminated with cat feces [15].

CONCLUSION

Toxoplasmosis is a zoonosis disease on animals that can be spread to human. It is caused by sporozoa that called T. gondii, which a intracellular parasite which infecting human and animals. Toxoplasmosis disease usually spread by cat but also can infect pig, sheep, and livestock animals. The prevalence rates of toxoplasmosis among HIV are greatly varied from 3% to 97%. It is usually related to ethnicity, certain risk factors, and reactivation of toxoplasmosis. This disease classified into acute and chronic stages. The acute or early stage is mostly associated with the proliferative form (tachyzoite) while the tissues cyst is predominant from during chronic infection, although tachyzoites have been reported outside cyst at this stage. The progression of the infection can lead to confusion, drowsiness, hemiparesis, hemianopsia, aphasia, ataxia, and cranial nerve palsies. Motor weakness and speech disturbance are seen as the disease progresses. The risk factors of Toxoplasma infection in HIV-infected patients include age, race/ethnicity, other demographic characteristics, unhygenic person, exposed to cat or cats feces and unwashed hand after gardening or doing activity involving soil. To diagnose toxoplasmosis, blood test, MRI, CT scan and CBP fluid can be done. Finally, the theraphy for acute toxoplasmosis in HIVinfected patients is pyrimethamine and sulfadiazine.

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