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 world’s 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 world’s 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)¼20 mm, in (E) to (G) ¼10 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)

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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 CD 4+¿ ¿

cells. This impairment correlates with the decreased production of IL-12 and IFN-ᵞin

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 CD 4+¿ ¿ count decreases below

100cell/μL [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 Malay’s 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

5

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 patient’s 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

patient’s 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

7

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 patient’s 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 cell-

mediated 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].

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(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

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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

10

infection in HIV-infected patients include age, race/ethnicity, other demographic

characteristics, unhygenic person, exposed to cat or cat’s 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 HIV-

infected patients is pyrimethamine and sulfadiazine.

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