Penyakit Dalam - Tropis Dan Infeksi - Malaria

7/28/2019 Penyakit Dalam - Tropis Dan Infeksi - Malaria

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MALARIA

10/6/2011 Penyakit Dalam Penyakit Tropis & Infeksi

Pembahasan mengenai Malaria; etiologi, pathogenesis,

patofisiologi, metode diagnosis, manajemen dan terapi.


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MalariaB A C K G R O U N D

Malaria adalah penyakit karena protozoa yang ditularkan melalui gigitan nyamuk. Penyakit ini

merupakan penyakit karena parasit yang LUAR BIASA, karena tingkat persebarannya

melibatkan 107 negara dengan populasi total sekitar 3 milyar penduduk, dan faktanya Malaria

MENYEBABKAN 1-3 juta KEMATIAN tiap tahun. Yang menarik adalah, Amerika Serikat, Canada,

Eropa dan Rusia mampu meminimalkan angka kejadian penyakit ini, NAMUN kenyataanya,

Indonesia termasuk dalam Negara dengan angka kejadian Malaria yang cukup tinggi di dunia.

Keadaan lain menunjukkan adanya masalah resistensi obat yang makin meluas. Sehingga yang

masih terjadi sekarang ini adalah makin meningkatnya kejadian Malaria di daerah tropis,ancaman bagi Negara-negara non endemik, dan bahaya bagi para wisatawan antar Negara!

Jadiapa obat untuk menyembuhkan penyakit Malaria ini? Jawabannya adalah TAHU

SEGALA SESUATU tentang MALARIA dan APA yang terjadi pada PASIEN MALARIA

ETIOLOGI | Malaria

Sebenarnya siapa yang menjadi penyebab penyakit Malaria? Mereka adalah PROTOZOAINTRASELULER; yaitu Plasmodium. Empat jenis paling penting yang menyebabkan penyakit pada

manusia adalah : Plasmodium vivax, P. ovale, P. malariae dan P. falciparum.

Mari kita kenali dulu morfologi dari Plasmodium ini. Pada apusan darah yang sudah diberi pewarnaan,

ada 3 komponen penting untuk mengenali gambaran Plasmodium. Mari kita bayangkan; ada kromatin

berwarna merah, didalam sitoplasma berwarna biru, dengan tambahan pigmen malaria berwarna

coklat kehitaman, atau yang disebut hemozoin, berisi sejumlah besar hasil degradasi fibrin,

ferriprotoporphyrin IX. Sesuatu yang MEMUDAHKAN adalah, perubahan bentuk sitoplasma dan

pembelahan dari kromatin pada tahap berbeda dari perkembangan parasit SANGAT JELAS TERLIHAT!

Gametosit dapat dengan mudah dibedakan dari bentuk aseksualnya karena ukurannya yang lebihbesar dan sedikit pembelahan inti. Yang lebih menarik lagi untuk dicermati adalah, eritrosit yang

terinfeksi membentuk invaginasi pada membrane (atau disebut kompleks caveolae-vesikel), yang

membentuk gambaran khas bintik Schuffner!


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Anda pasti ingin TAHU lebih jauh mengenai CIRI KHAS yang MENARIK dari masing-masing

Plasmodium. Cermati rincian di halaman setelah ini!

Karakteristik P. vivax P. ovale P. malariae P. falciparum

Eritrosit

Membesar, pucat

Oval, berfimbria

Bintik Schuffner

Bintik Maurer

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Parasit

Semua tahap seksual terlihat

Bentuk seperti pita

Bintik kromatin dobel

Gametosit berbentuk pisang

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Hal UNIK dari Protozoa tersebut adalah fase reproduksinya, yaitu REPRODUKSI SEKSUAL dan

ASEKSUAL. Kenapa ASEKSUAL? Ternyata protozoa mampu melakukan multiplikasi (penggandaan diri)dengan prosesfission multiple yang disebut dengan schizogony. Nukleus dari tropozoitnya akan terbagi

menjadi beberapa bagian sehingga membentuk schizont multinukleus. Sitoplasma selanjutnya akan

bergabung dengan sebagian inti sel dan membentuk sel anakan yang baru, atau disebut MEROZOIT,

yang akan melebur kedalam lokasi intraseluler untuk menginvasi sel inang. Sesudah melewati tahap

aseksual, merozoit yang terbentuk akan berdiferensiasi menjadi gametosit jantan dan betina, yang

nantinya akan mengawali siklus reproduksi SEKSUAL yang disebut SPOROGONY. Gametosit yang

dewasa dan hasil fertilisasi akan membentuk ZYGOT atau dalam bentuk aktif disebut OOSIT. Ketika

oosit dikeluarkan akan terbentuklah SPOROZOIT yang akan masuk ke dalam jaringan dan sel inang dan

memulai kembali siklus ASEKSUAL.

Nah, karena ada 2 fase reproduksi itulah nyamuk Anopheles menjadi vector penting bagi penularan

Malaria, KENAPA? Karena ternyata fase SEKSUAL terjadi didalam USUS NYAMUK. Nyamuk menularkan

Plasmodium ketika menghisap darah dari inang, salah satunya kita, MANUSIA. Didalam sel darah


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merah makhluk vertebra selanjutnya Plasmodium mengalami reproduksi secara ASEKSUAL;

Plasmodium akan menginvasi sel darah merah.

LIFE CYCLE OF MALARIAL PARASITES

Sporogony, or the sexual cycle, begins when a female mosquito of the genus Anopheles ingests

circulating male and female gametocytes while feeding on a malarious human. In the gut of the

mosquito, the gametocytes mature and effect fertilization. The resulting zygote penetrates the

mosquitos gut wall, lodges beneath the basement membrane, and vacuolates to form a n oocyst.

Within this structure, thousands of sporozoites are formed. The enlarging cyst eventually ruptures,

releasing the sporozoites into the body cavity of the mosquito. Some penetrate the salivary glands,

rendering the mosquito infectious for humans. The time required for the completion of the cycle inmosquitoes varies from 1 to 3 weeks, depending on the species of insect and parasite as well as on the

ambient temperature and humidity. Schizogony, the asexual cycle, occurs in the human and begins

when the infected Anopheles takes a blood meal from another individual. Sporozoites from the

mosquitos salivary glands are injected into the humans subcutaneous capillaries and circulate in the

peripheral blood. Within 1 hour they attach to and invade liver cells (hepatocytes), a process thought

to be mediated by a ligand present in the sporozoites outer protein coat (circumsporozoite protein). In

P. vivax and P. ovale infections, some of the sporozoites enter a dormant state immediately after cell

invasion. The remaining sporozoites initiate exoerythrocytic schizogony, each producing about 2000 to

40,000 daughter cells, or merozoites. One to two weeks later, the infected hepatocytes rupture,

releasing merozoites into the general circulation. The erythrocytic phase of malaria starts with the

attachment of a released hepatic merozoite to a specific receptor on the RBC surface. After

attachment, the merozoite invaginates the cell membrane and is slowly endocytosed. The intracellular

parasite initially appears as a ring-shaped trophozoite, which enlarges and becomes more active and

irregular in outline. Within a few hours, nuclear division occurs, producing the multinucleated schizont.

Cytoplasm eventually condenses around each nucleus of the schizont to form an intraerythrocytic

cluster of 6 to 24 merozoite daughter cells. About 48 (P. vivax, P. ovale, and P. falciparum) to 72 (P.

malariae) hours after initial invasion, infected erythrocytes rupture, releasing the merozoites and

producing the first clinical manifestations of disease. The newly released daughter cells invade other

RBCs, where most repeat the asexual cycle. Other daughter cells are transformed into sexual forms orgametocytes. These latter forms do not produce RBC lysis, and continue to circulate in the peripheral

vasculature until ingested by an appropriate mosquito. The recurring asexual cycles continue, involving

an ever-increasing number of erythrocytes until finally the development of host immunity brings the

erythrocytic cycle to a close. The dormant hepatic sporozoites of P. vivax and P. ovale survive the

hosts immunologic attack, and may, after a latent period of months to years, resume intrahepatic


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multiplication. This leads to a second release of hepatic merozoites and the initiation of another

erythrocytic cycle, a phenomenon known as relapse.

Species of plasmodia differ significantly in their ability to invade subpopulations of erythrocytes; P.

vivax and P. ovale attack only immature cells (reticulocytes), whereas P. malariae attacks only

senescent cells. During infection with these species, therefore, no more than 1 to 2% of the cell

population is involved. P. falciparum, in contrast, invades RBCs regardless of age and may produce very

high levels of parasitemia and particularly serious disease. In part, these differences may be related to

the known differences in the RBC receptor sites available to the individual Plasmodium species. In the

case of P. vivax, the site is closely related to the Duffy blood group antigens (Fya and Fyb). Duffy-

negative individuals, who constitute the majority of people of West African ancestry, are therefore

resistant to vivax malaria. RBC sialoglycoprotein, particularly glycoprotein A, has been implicated as the

P. falciparum receptor site. Certain RBC abnormalities may also effect parasitism. The altered

hemoglobin (hemoglobin S) associated with the sickle cell trait limits the intensity of the parasitemia

caused by P. falciparum, and thereby provides a selective advantage to individuals who areheterozygous for the sickle cell gene. As a result, the sickle cell gene, which would otherwise be

disadvantageous, is found at high frequency in populations living in malarious areas. Parasite growth

appears to be retarded in RBCs heterozygous for hemoglobin S (SA) when they are exposed to

conditions of reduced oxygen tension such as might be present in the visceral capillaries. Sickling may

also render the erythrocyte more susceptible to phagocytosis or directly damage the parasite. A similar

protective effect may be exerted by hemoglobins C, D, and E; thalassemias; and glucose-6-phosphate

dehydrogenase (G6PD) or pyridoxal kinase deficiencies, because these abnormalities have also been

found more frequently in malarious areas. The protection in these conditions may be related to the

increased susceptibility of such RBCs to oxidant stress. In thalassemia, the protection may also berelated in part to the production of fetal hemoglobin, which retards maturation of P. falciparum, as

well as an increased binding of antibodies to modified parasitic antigens (neoantigens) presenting on

the surface of the erythrocytes.

Once invasion has occurred, malaria parasites may induce a number of changes in the erythrocytic

membrane. These include alteration of its lipid concentration, modification of its osmotic properties,

and incorporation of parasitic neoantigens, rendering the RBC susceptible to immunologic attack. P.

vivax and P. ovale stimulate the production of caveolaevesicle complexes, which are visualized as

Schffners dots in stained smears. In P. falciparum infections, electron-dense elevated knobs or

excrescences form on the RBC surface. These produce a strain specific, high-molecular-weight adhesiveprotein (PfEMP1), which mediates binding to receptors on the endothelium of capillaries and

postcapillary venules of the brain, placenta, and other organs, where they can produce obstruction and

microinfarcts.


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Malarial parasites generate energy by the anaerobic metabolism of glucose. They appear to satisfy

their protein requirements by the degradation of hemoglobin within their acidic food vacuoles,

resulting in the formation of the malarial pigment (hemozoin) mentioned previously. It has been

estimated that the average plasmodium destroys between 25 and 75% of the hemoglobin of its host

erythrocyte. Unlike their vertebrate hosts, malarial parasites synthesize folates de novo. As a result,antifolate antimicrobics such as pyrimethamine are effective antimalarial agents.

PENTING bagi Anda untuk menyiapkan gambaran sirkulasi darah normal untuk memudahkan dalam

mengimajinasikan mekanisme infeksi Plasmodium ini. Siap?

Human infection begins when a female anopheline mosquito inoculates plasmodial

sporozoites from its salivary gland during a blood meal (Fig. 203-1). These

microscopic motile forms of the malarial parasite are carried rapidly via the

bloodstream to the liver, where they invade hepatic parenchymal cells and begin a

period of asexual reproduction. By this amplification process (known as intrahepatic

or preerythrocyticschizogony or merogony), a single sporozoite eventually may

produce from 10,000 to >30,000 daughter merozoites. The swollen infected liver cell

eventually bursts, discharging motile merozoites into the bloodstream. These then

invade the red blood cells (RBCs) and multiply six- to twentyfold every 48

72 h. When

the parasites reach densities of ~50/ L of blood, the symptomatic stage of the

infection begins. In P. vivaxand P. ovale infections, a proportion of the intrahepatic

forms do not divide immediately but remain dormant for a period ranging from 3

weeks to a year or longer before reproduction begins. These dormant forms, or

hypnozoites, are the cause of the relapses that characterize infection with these two

species.

PATOFISIOLOGI | Malaria

Fever

Fever, the hallmark of malaria, appears to be initiated by the process of RBC rupture that leads to the

liberation of a new generation of merozoites (sporulation). To date, all attempts to detect the factor(s)


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mediating the fever have been unsuccessful. It is possible that parasite-derived pyrogens are released

at the time of sporulation; alternatively, the fever might result from the release of interleukin-1 (IL-1)

and/or tumor necrosis factor (TNF) from macrophages involved in the ingestion of parasitic or

erythrocytic debris. Early in malaria, RBCs appear to be infected with malarial parasites at several

different stages of development, each inducing sporulation at a different time. The resulting fever isirregular and hectic. Because temperatures in excess of 40C destroy mature parasites, a single

population eventually emerges, sporulation is synchronized, and fever occurs in distinct paroxysms at

48-hour or, in the case of P. malariae, 72-hour intervals. Periodicity is seldom seen in patients who are

rapidly diagnosed and treated.

Anemia

Parasitized erythrocytes are phagocytosed by a stimulated reticuloendothelial system or are destroyed

at the time of sporulation. At times, the anemia is disproportionate to the degree of parasitism.

Depression of marrow function, sequestration of erythrocytes within the enlarging spleen, andaccelerated clearance of nonparasitized cells all appear to contribute to the anemia. The mechanisms

responsible for the latter are unclear. Intravascular hemolysis, although uncommon, may occur,

particularly in falciparum malaria. When hemolysis is massive, hemoglobinuria develops, resulting in

the production of dark urine.This process in conjunction with malaria is known as blackwater fever.

Circulatory Changes

The high fever results in significant vasodilatation. In falciparum malaria, vasodilatation leads to a

decrease in the effective circulating blood volume and hypotension, which may be aggravated by other

changes in the small vessels and capillaries. The intense parasitemias P. falciparum is capable of

producing and the adhesion of infected RBCs to the endothelium of visceral capillaries can impair the

microcirculation and precipitate tissue hypoxia, lactic acidosis, and hypoglycemia. Although all deep

tissues are involved, the brain is the most intensely affected.

Cytokines

Elevated levels of IL-1 and TNF are consistently found in patients with malaria. Probably released at the

time of sporulation, these proteins are certainly an essential part of the hosts immune response to

malaria (see below). By modulating the effects of endothelial cells, macrophages, monocytes, and

neutrophils, they may play an important role in the destruction of the invading parasite. However, TNF

levels increase with parasite density and high concentrations appear harmful. TNF has been shown tocause upregulation of endothelial adhesion molecules; high concentrations might precipitate cerebral

malaria by increasing the sequestration of P. falciparumparasitized erythrocytes in the cerebral

vascular endothelium. Alternatively, excessive TNF levels might precipitate cerebral malaria by directly

inducing hypoglycemia and lactic acidosis.


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METODE DIAGNOSA | Malaria

ETIOLOGI | Malaria

ETIOLOGI | Malaria

Penyakit Dalam - Tropis Dan Infeksi - Malaria

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