Malaria

Introduction

Malaria is a serious and sometimes fatal disease caused by a parasite called Plasmodium that commonly infects a certain type of mosquito which feeds on humans. In the human body, the parasites multiply in the liver, and then infect red blood cells. People who get malaria are typically very sick with high fevers, shaking chills, and flu-like illness and usually appear between 10 and 15 days after the mosquito bite.. Although malaria can be a deadly disease, illness and death from malaria can usually be prevented. In many parts of the world, the parasites have developed resistance to a number of malaria medicines.

About 1,500 cases of malaria are diagnosed in the United States each year. The vast majority of cases in the United States are in travelers and immigrants returning from countries where malaria transmission occurs, many from sub-Saharan Africa and South Asia.

Epidemiology

Picture1. The distribution of malaria in the world.

Malaria occurs throughout most of the tropical regions of the world. P. falciparum predominates in Africa, New Guinea, and Haiti; P. vivax is more common in Central America. The prevalence of these two species is approximately equal in South America, the Indian subcontinent, eastern Asia, and Oceania. P. malariae is found in most endemic areas, especially throughout sub-Saharan Africa, but is much less common. P. ovale is relatively unusual outside of Africa and, where it is found, comprises.

Approximately 40% of the world's population live in endemic areas and are at risk for malaria. An estimated 350-500 million malaria cases occur each year, and more than one million people die of the infection.

Malaria is responsible for approximately 1-3 million deaths per year, typically in children in sub-Saharan Africa infected with P falciparum. Populations at an increased risk for mortality due to malaria

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include primigravida individuals, travelers without immunity, and young children aged 6 months to 3 years who live in endemic areas.

Young children aged 6 months to 3 years who live in endemic areas are at an increased risk of death due to malaria. Travelers without immunity are at an increased mortality risk, regardless of age.

In Indonesia, the endemic of Malaria is still high. Malaria is concentrated on the outer islands of Papua, Maluku, Nusa Tenggara, Sulawesi, Kalimantan and Sumatra. It occurs with low frequency or is absent on the islands of Java and Bali where approximately 70% of the population live. All species of human malaria parasites are found in Indonesia. Formerly, P. malariae and P. ovale were mostly found in the eastern part of Indonesia, Nusa Tenggara Timur and Papua. Around 107 million people are at varied degrees of risk. Malaria transmission in Indonesia is perennial. P. vivax and P. falciparum are the most common types of malaria species prevalent in the country.

Picture 2. Malaria endemicity level in Indonesia, 2005

Etiology and Pathogenesis

The etiology of malaria is the four species of the genus Plasmodium cause nearly all malarial infections in humans (although rare infections involve species normally affecting other primates). These are P. falciparum, P. vivax, P. ovale, and P. malariae. Almost all deaths are caused by falciparum Malaria.

Picture 3. Malaria transmission cycle.

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Human infection begins when a female anopheline mosquito inoculates plasmodial sporozoites from its salivary gland during a blood meal. 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/µL of blood, the symptomatic stage of the infection begins. In P. vivax and 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.

Picture 4 and 5. Developmental stages of P. vivax, P. ovale, P. malariae, and P. falciparum

After entry into the bloodstream, merozoites rapidly invade erythrocytes and become trophozoites. Attachment is mediated via a specific erythrocyte surface receptor. In the case of P. vivax, this receptor is related to the Duffy blood-group antigen Fya or Fyb. Most West Africans and people with origins in that region carry the Duffy-negative FyFy phenotype and are therefore resistant to P. vivax Malaria.During the early stage of intraerythrocytic development, the small "ring forms" of the four parasitic species appear similar under light microscopy. As the trophozoites enlarge, species-specific characteristics become evident, pigment becomes visible, and the parasite assumes an irregular or ameboid shape. By the end of the 48-h intraerythrocytic life cycle (72 h for P. malariae), the parasite has consumed nearly all the hemoglobin and grown to occupy most of the RBC. It is now called a schizont. Multiple nuclear divisions have taken place (schizogony or merogony), and the RBC then ruptures to release 6–30 daughter merozoites, each potentially capable of invading a new RBC and repeating the cycle. The disease in human beings is caused by the direct effects of RBC invasion and destruction by the asexual parasite and the host's reaction. After a series of asexual cycles (P. falciparum) or immediately after release from the liver (P. vivax, P. ovale, P. malariae), some of the parasites develop into morphologically distinct, longer-lived sexual forms (gametocytes) that can transmit Malaria. After being ingested in the blood meal of a biting female anopheline mosquito, the male and female gametocytes form a zygote in the insect's midgut. This zygote matures into an ookinete, which penetrates and encysts in the mosquito's gut wall. The resulting oocyst expands by asexual division until it bursts to liberate myriad motile sporozoites, which then migrate in the hemolymph to the salivary gland of the mosquito to await inoculation into another human at the next feeding.

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aParasitemias of >2% are suggestive of P. falciparum infection

Table 1. Characteristics of Plasmodium sp infecting humans

Erythrocyte Changes in Malaria

After invading an erythrocyte, the growing malarial parasite progressively consumes and degrades intracellular proteins, principally hemoglobin. The potentially toxic heme is detoxified by polymerization to biologically inert hemozoin (Malaria pigment). The parasite also alters the RBC membrane by changing its transport properties, exposing cryptic surface antigens, and inserting new parasite-derived proteins. The RBC becomes more irregular in shape, more antigenic, and less deformable.

In P. falciparum infections, membrane protuberances appear on the erythrocyte's surface 12–15 h after the cell's invasion. These "knobs" extrude a high-molecular-weight, antigenically variant, strain-specific erythrocyte membrane adhesive protein (PfEMP1) that mediates attachment to receptors on venular and capillary endothelium—an event termed cytoadherence. Several vascular receptors have been identified, of which intercellular adhesion molecule 1 (ICAM-1) is probably the most important in the brain, chondroitin sulfate B in the placenta, and CD36 in most other organs. Thus, the infected erythrocytes stick inside and eventually block capillaries and venules. At the same stage, these P. falciparum–infected RBCs may also adhere to uninfected RBCs (to form rosettes) and to other parasitized erythrocytes (agglutination). The processes of cytoadherence, rosetting, and agglutination are central to the pathogenesis of falciparum Malaria. They result in the sequestration of RBCs containing mature forms of the parasite in vital organs (particularly the brain), where they interfere with microcirculatory flow and metabolism. Sequestered parasites continue to develop out of reach of the principal host defense mechanism: splenic processing and filtration. As a consequence, only the younger ring forms of the asexual parasites are seen circulating in the peripheral blood in falciparum Malaria, and the level of peripheral parasitemia underestimates the true number of parasites within the body. Severe Malaria is also associated with reduced deformability of the uninfected erythrocytes, which compromises their passage through the partially obstructed capillaries and venules and shortens RBC survival.

In the other three ("benign") malarias, sequestration does not occur, and all stages of the parasite's development are evident on peripheral blood smears. Whereas P. vivax, P. ovale, and P. malariae show a marked predilection for either young RBCs (P. vivax, P. ovale) or old cells (P. malariae)

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and produce a level of parasitemia that is seldom >2%, P. falciparum can invade erythrocytes of all ages and may be associated with very high levels of parasitemia.

Host Response

Initially, the host responds to plasmodial infection by activating nonspecific defense mechanisms. Splenic immunologic and filtrative clearance functions are augmented in Malaria, and the removal of both parasitized and uninfected erythrocytes is accelerated. The parasitized cells escaping splenic removal are destroyed when the schizont ruptures. The material released induces the activation of macrophages and the release of proinflammatory mononuclear cell–derived cytokines, which cause fever and exert other pathologic effects. Temperatures of ≥ 40°C damage mature parasites; in untreated infections, the effect of such temperatures is to further synchronize the parasitic cycle, with eventual production of the regular fever spikes and rigors that originally served to characterize the different malarias. These regular fever patterns (tertian, every 2 days; quartan, every 3 days) are seldom seen today in patients who receive prompt and effective antimalarial treatment.

The geographic distributions of sickle cell disease, ovalocytosis, thalassemia, and glucose-6-phosphate dehydrogenase (G6PD) deficiency closely resemble that of Malaria before the introduction of control measures. This similarity suggests that these genetic disorders confer protection against death from falciparum Malaria. For example, HbA/S heterozygotes (sickle cell trait) have a sixfold reduction in the risk of dying from severe falciparum Malaria. This decrease in risk appears to be related to impaired parasite growth at low oxygen tensions. Parasite multiplication in HbA/E heterozygotes is reduced at high parasite densities.

In Melanesia, children with -thalassemia appear to have more frequentα Malaria (both vivax and falciparum) in the early years of life, and this pattern of infection appears to protect against severe disease. In Melanesian ovalocytosis, rigid erythrocytes resist merozoite invasion, and the intraerythrocytic milieu is hostile.

Nonspecific host defense mechanisms stop the infection's expansion, and the subsequent specific immune response controls the infection. Eventually, exposure to sufficient strains confers protection from high-level parasitemia and disease but not from infection. As a result of this state of infection without illness (premunition), asymptomatic parasitemia is common among adults and older children living in regions with stable and intense transmission (i.e., holo- or hyperendemic areas). Immunity is mainly specific for both the species and the strain of infecting malarial parasite. Both humoral immunity and cellular immunity are necessary for protection, but the mechanisms of each are incompletely understood. Immune individuals have a polyclonal increase in serum levels of IgM, IgG, and IgA, although much of this antibody is unrelated to protection. Antibodies to a variety of parasitic antigens presumably act in concert to limit in vivo replication of the parasite. In the case of falciparum Malaria, the most important of these antigens is the surface adhesin—the variant protein PfEMP1 mentioned above. Passively transferred IgG from immune adults has been shown to reduce levels of parasitemia in children; although parasitemia in very young infants can occur, passive transfer of maternal antibody contributes to the relative (but not complete) protection of infants from severe Malaria in the first months of life. This complex immunity to disease declines when a person lives outside an endemic area for several months or longer.

Several factors retard the development of cellular immunity to Malaria. These factors include the absence of major histocompatibility antigens on the surface of infected RBCs, which precludes direct T cell recognition; Malaria antigen–specific immune unresponsiveness; and the enormous strain diversity

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of malarial parasites, along with the ability of the parasites to express variant immunodominant antigens on the erythrocyte surface that change during the period of infection. Parasites may persist in the blood for months (or, in the case of P. malariae, for many years) if treatment is not given. The complexity of the immune response in Malaria, the sophistication of the parasites' evasion mechanisms, and the lack of a good in vitro correlate with clinical immunity have all slowed progress toward an effective vaccine.

Clinical Features

Malaria is a very common cause of fever in tropical countries. The first symptoms of Malaria are nonspecific; the lack of a sense of well-being, headache, fatigue, abdominal discomfort, and muscle aches followed by fever are all similar to the symptoms of a minor viral illness. In some instances, a prominence of headache, chest pain, abdominal pain, arthralgia, myalgia, or diarrhea may suggest another diagnosis. Although headache may be severe in Malaria, there is no neck stiffness or photophobia resembling that in meningitis. While myalgia may be prominent, it is not usually as severe as in dengue fever, and the muscles are not tender as in leptospirosis or typhus. Nausea, vomiting, and orthostatic hypotension are common. The classic malarial paroxysms, in which fever spikes, chills, and rigors occur at regular intervals, are relatively unusual and suggest infection with P. vivax or P. ovale. The fever is irregular at first (that of falciparum Malaria may never become regular); the temperature of nonimmune individuals and children often rises above 40°C in conjunction with tachycardia and sometimes delirium. Although childhood febrile convulsions may occur with any of the malarias, generalized seizures are specifically associated with falciparum Malaria and may herald the development of cerebral disease. Many clinical abnormalities have been described in acute Malaria, but most patients with uncomplicated infections have few abnormal physical findings other than fever, malaise, mild anemia, and (in some cases) a palpable spleen. Anemia is common among young children living in areas with stable transmission, particularly where resistance has compromised the efficacy of antimalarial drugs. In nonimmune individuals with acute Malaria, the spleen takes several days to become palpable, but splenic enlargement is found in a high proportion of otherwise healthy individuals in Malaria -endemic areas and reflects repeated infections. Slight enlargement of the liver is also common, particularly among young children. Mild jaundice is common among adults; it may develop in patients with otherwise uncomplicated falciparum Malaria and usually resolves over 1–3 weeks. Malaria is not associated with a rash like those seen in meningococcal septicemia, typhus, enteric fever, viral exanthems, and drug reactions. Petechial hemorrhages in the skin or mucous membranes—features of viral hemorrhagic fevers and leptospirosis—develop only rarely in severe falciparum Malaria.

Picture 6. Fever in malaria tertian, kuartana and continue

Diagnosis

a. Anamnesis

b. Physical examination

c. Supporting examination

- Thin smear

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- Thick smear

- PHRP2 dipstick

- Plasmodium LDH dipstick

- Microtube concentration method

Table 2. Methods for the diagnosis of Malaria

Treatment

A.Treatment of acute attacks

1. Elimination of asexual erythrocytic parasites

- chloroquine phosphate (salt) 1g at 0, 24, and then 0.5 g at 48 hours

- mefloquine : 1 x 250 mg for 3 days, or 750-1250 mg, then 500 mg after 6-8 hours

- quinine sulfate (plus doxycycline, clindamycin, or fansidar)

- atovaquone 250 mg (plus doxycycline 100 mg or proguanil 100 mg)

- halofantrine,

- artemisinin (qinghaosu), fisrt day 2x2 tabs, then 2x1 tablet for 5 days

in severe patients - start oral therapy with chloroquine as soon as possible

- IV quinine dihydrochloride

- quinidine gluconate

- parenteral chloroquine

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2. eradication of p. vivax or p. ovale : chloroquine as above followed by 0.5 g on days 10 and 17 plus primaquine phosphate, 25,3 mg (salt) daily for 14 days starting about day 4.

3. elimination of persistent gametocytemia : - chloroquine for p.vivax, p. ovale, p. malariae

- primaquine salt, single dose, 26.3 mg for p. falciparum

Treatment of falciparum malaria acquired in areas where p. falciparum is resistant to chloroquine :

- start with oral quinine sulfate, 10 mg/kg 3x daily for 3-7 days, plus :

~ doxycycline, 2x100 mg daily for 7 days

~ clindamycin. 3x900 mg daily for 5 days

~ pyrimethamine, 2x25 mg daily for 3 days

~ sulfadiazine, 4x500 mg daily for 7 days

~ 3 tablets of fansidar (pyrimethamin+ sulfadoxine)

- severely ill:

~ iv quinine or quinidine

~ docycycline or clindamycin parentrally

- oral treatment with quinine plus the antibiotic should be as soon as possible

* special treatment for treatment of severe p. falciparum malaria

- medical emergency that requires:

~ hospitalization

~ intensive care

~ iv chemotherapy as rapid as possible

~ requiring >48 hour of parentral therapy

~ dehydration should be done with caution

~ fluid, electrolyte & acid- base balance must be monitored

~ early dialysis may be necessary for renal failure

~ blood glucose levels should be monitored every 6 hours if hypoglycemia + 50% dextrose, 1-2 ml/kg maintenance 5-10% dextrose

- dic fresh whole blood

- hct < 20% transfusion

- exchange transfusion when >15% rbc are parasitized

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- seizures anticonvulsants

- temperature is maintained <38.5 ºc

b. chemoprophylaxis (1)

a. in regions where p. falciparum and p. vivax are sensitive to chloroquine

~ drug of choice

1. chloroquine phosphate, 500 mg weekly, one week before entering the endemic area, while there, and for 4 week after leaving

b. in regions where p. falciparum is resistant to chloroquinine

~ drugs of choice : mefloquine salt, 250 mg (228 mg base) weekly, 1-3 weeks before entering the endemic area, while there, and for 4 weeks after leaving.

~ alternative: - first alternative: doxycycline, 100 mg daily, 2 days before entering the endemic area, while there, and for 4 weeks after leaving

- second alternative: malarone (atovaquone 250 mg + proguanil 100 mg), one tablet daily, one tablet the day before entering the endemic area, while there, and for 1 week after leaving

- other alternatives: daily proguanil 200 mg + weekly chloroquine 0.5 g, more protection than chloroquine alone

c. prophylaxis for pregnant women

- the best course is weekly chloroquine +/– proguanil

- in areas of chloroquine-resistant malaria mefloquinine, except in the first trimester

- drugs contraindicated are doxycycline & primaquine

Prevention

Key interventions to control malaria include:

prompt and effective treatment with artemisinin-based combination therapies;

use of insecticidal nets by people at risk; and

indoor residual spraying with insecticide to control the vector mosquitoes.

Prognosis

Good if patient get early treatment and poor in late case.

Complication

Anemia Renal failure

Pulmonary edema

Hyperpyrexia

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Circulatory collapse (algid malaria)

Jaundice

References :

1. WHO. Malaria. 2011. http://www.who.int/topics/malaria/en/ 2. CDC. Malaria. 2010.http://www.cdc.gov/malaria/about/index.html

3. CDC. Where Malaria Occur. 2010. http://www.cdc.gov/malaria/about/distribution.html

4. Fauce et al. Harrison's Internal Medicine. 2008. Chapter 203. Malaria

5. Jorge, EVP. Malaria. 2011. http://emedicine.medscape.com/article/221134-overview#a0199

6. WHO. 2005. Acces from http://www.searo.who.int/LinkFiles/Malaria_in_the_SEAR_ende_indo05.pdf

7. Mcphee, SJ ; Papadakis, MA. Current Medical Diagnosis and Treatment. 2009. Chapter 35. Protozoal & Helminthic Infections > Protozoal Infections

8. Jorge, EVP. Malaria. http://emedicine.medscape.com/article/221134-workup

9. Bahan kuliah, Mubin, R. Malaria. 2011

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