1 CHAPTER 1 INTRODUCTION Malaria is a common and life-threatening disease in many tropical and subtropical areas. There are currently over 100 countries and territories where there is a risk of malaria transmission. Malaria is caused by intracellular Plasmodium protozoa transmitted to humans by female Anopheles mosquitoes. Prior to 2004, only 4 species of Plasmodium were known to cause malaria in humans: P. falciparum, P. malariae, P. ovale, and P. vivax. In 2004 P. knowlesi (a primate malaria species) was also shown to cause human malaria, and cases of P. knowlesi infection have been documented in Malaysia, Indonesia, Singapore, and the Philippines. Malaria also can be transmitted through blood transfusion, use of contaminated needles, and from a pregnant woman to her fetus. 1 Malaria typically results in flulike symptoms that appear 9–14 days after an infectious mosquito bite. Initial symptoms can include headache, fatigue and aches in the muscles and joints, fever, chills, vomiting and diarrhea; they can quickly progress into severe disease and death. Among young children fever is the most common symptom of malaria. 3
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1
CHAPTER 1
INTRODUCTION
Malaria is a common and life-threatening disease in many tropical and
subtropical areas. There are currently over 100 countries and territories where there is
a risk of malaria transmission. Malaria is caused by intracellular Plasmodium
protozoa transmitted to humans by female Anopheles mosquitoes. Prior to 2004, only
4 species of Plasmodium were known to cause malaria in humans: P. falciparum, P.
malariae, P. ovale, and P. vivax. In 2004 P. knowlesi (a primate malaria species) was
also shown to cause human malaria, and cases of P. knowlesi infection have been
documented in Malaysia, Indonesia, Singapore, and the Philippines. Malaria also can
be transmitted through blood transfusion, use of contaminated needles, and from a
pregnant woman to her fetus.1
Malaria typically results in flulike symptoms that appear 9–14 days after an
infectious mosquito bite. Initial symptoms can include headache, fatigue and aches in
the muscles and joints, fever, chills, vomiting and diarrhea; they can quickly progress
into severe disease and death. Among young children fever is the most common
symptom of malaria.3
Malaria is of overwhelming importance in the developing world today, with an
estimated 3 billion people, almost half the world’s population, live in areas where
malaria transmission occurs. Malaria is endemic in 107 countries and territories in
tropical and subtropical regions, with sub-Saharan Africa hardest hit. Between 350
million and 500 million cases of clinical malaria occur each year, leading to an
estimated 1 million deaths. Most malarial deaths occur among infants and young
children. Indonesia is one of the countries that are endemic for Malaria. Data form
2009 lists around 80% of districts in Indonesia to be endemic while 45% of
populations live in places that are high risk for malarial transmission. A national
survey in 2001 stated that the death rate due to malaria was 11 per 100,000 for male
and 8 per 100,000 for females respectively.5
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CHAPTER 2
LITERATURE REVIEW
2.1 Definition
Malaria is an acute and chronic illness characterized by paroxysms of fever, chills,
sweats, fatigue, anemia, and splenomegaly. Malaria is caused by intracellular
Plasmodium protozoa transmitted to humans by female Anopheles mosquitoes. Prior to
2004, only 4 species of Plasmodium were known to cause malaria in humans: P.
falciparum, P. malariae, P. ovale, and P. vivax. In 2004 P. knowlesi (a primate malaria
species) was also shown to cause human malaria. Malaria also can be transmitted
through blood transfusion, use of contaminated needles, and from a pregnant woman to
her fetus.2
2.2 Epedimiology
Malaria is a major worldwide problem, occurring in more than 100 countries with a
combined population of over 1.6 billion people. According to the latest estimates,
198 million cases of malaria occurred globally in 2013 and the disease led to 584 000
deaths. The principal areas of transmission are Africa, Asia, and South America. P.
falciparum and P. malariae are found in most malarious areas. P. falciparum is the
predominant species in Africa, Haiti, and New Guinea. P. vivax predominates in
Bangladesh, Central America, India, Pakistan, and Sri Lanka. P. vivax and P.
falciparum predominate in Southeast Asia, South America, and Oceania. P. ovale is
the least common species and is transmitted primarily in Africa.3
Indonesia is one of the countries that is endemic for Malaria. Data form 2009 lists
around 80% of districts in Indonesia to be endemic while 45% of poppulation live in
places that are high risk for Malarial transmission. A national survey in 2001 stated
that the death rate due to malaria was 11 per 100,000 for male and 8 per 100,000 for
females respectively.10
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North Sumatera is one of the endemic areas in indonesia, the endemic areas incude
Deli Serdang, Labuhan Batu, Serdang Bedagai, Asahan, Samosir, Tapanuli Tengah,
North Tapanuli, Mandailing Natal, Nias, South Nias, Langkat, Batu Bara, Padang
Lawas, North Padang Lawas and Kabupaten Labuhan Batu.10
2.3 Plasmodium Life Cycle
Plasmodium species exist in a variety of forms and have a complex life cycle
that enables them to survive in different cellular environments in the human host
(asexual phase) and the mosquito (sexual phase). A marked amplification of
Plasmodium, from approximately 102 to as many as 1014 organisms, occurs during a 2-
step process in humans, with the 1st phase in hepatic cells (exoerythrocytic phase) and
the 2nd phase in the red cells (erythrocytic phase). The exoerythrocytic phase begins
with inoculation of sporozoites into the bloodstream by a female Anopheles mosquito.
Within minutes, the sporozoites enter the hepatocytes of the liver, where they develop
and multiply asexually as a schizont. After 1-2 wk, the hepatocytes rupture and
release thousands of merozoites into the circulation. The tissue schizonts of P.
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falciparum, P. malariae, and apparently P. knowlesi rupture once and do not persist in
the liver. There are 2 types of tissue schizonts for P. ovale and P. vivax. The primary
type ruptures in 6-9 days, and the secondary type remains dormant in the liver cell for
weeks, months, or as long as 5 yr before releasing merozoites and causing relapse of
infection.2
The erythrocytic phase of Plasmodium asexual development begins when the
merozoites from the liver penetrate erythrocytes. Once inside the erythrocyte, the
parasite transforms into the ring form, which then enlarges to become a trophozoite.
These latter 2 forms can be identified with Giemsa stain on blood smear, the primary
means of confirming the diagnosis of malaria (Fig. 280-3). The trophozoite multiplies
asexually to produce a number of small erythrocytic merozoites that are released into
the bloodstream when the erythrocyte membrane ruptures, which is associated with
fever. Over time, some of the merozoites develop into male and female gametocytes
that complete the Plasmodium life cycle when they are ingested during a blood meal
by the female anopheline mosquito. The male and female gametocytes fuse to form a
zygote in the stomach cavity of the mosquito. After a series of further
transformations, sporozoites enter the salivary gland of the mosquito and are
inoculated into a new host with the next blood meal.2
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2.4 Pathogenesis
Four important pathologic processes have been identified in patients with
malaria: fever, anemia, immunopathologic events, and tissue anoxia. Fever occurs
when erythrocytes rupture and release merozoites into the circulation. Anemia is
caused by hemolysis, sequestration of erythrocytes in the spleen and other organs, and
bone marrow suppression. Immunopathologic events that have been documented in
patients with malaria include excessive production of proinflammatory cytokines, such
as tumor necrosis factor, that may be responsible for most of the pathology of the
disease, including tissue anoxia; polyclonal activation resulting in both
hypergammaglobulinemia and the formation of immune complexes; and
immunosuppression. Cytoadherence of infected erythrocytes to vascular endothelium
occurs in P. falciparum malaria and may lead to obstruction of blood flow and
capillary damage, with resultant vascular leakage of blood, protein, and fluid and tissue
anoxia. In addition, hypoglycemia and lactic acidemia are caused by anaerobic
metabolism of glucose. The cumulative effects of these pathologic processes may lead
to cerebral, cardiac, pulmonary, intestinal, renal, and hepatic failure.6
Immunity after Plasmodium species infection is incomplete, preventing severe
disease but still allowing future infection. In some cases, parasites circulate in small
numbers for a long time but are prevented from rapidly multiplying and causing severe
illness. Repeated episodes of infection occur because the parasite has developed a
number of immune evasive strategies, such as intracellular replication, vascular
cytoadherence that prevents infected erythrocytes from circulating through the spleen,
rapid antigenic variation, and alteration of the host immune system resulting in partial
immune suppression. The human host response to Plasmodium infection includes
natural immune mechanisms that prevent infection by other Plasmodium species, such
as those of birds or rodents, as well as several alterations in erythrocyte physiology that
prevent or modify malarial infection. Erythrocytes containing hemoglobin S (sickle
erythrocytes) resist malaria parasite growth, erythrocytes lacking Duffy blood group
antigen are resistant to P. vivax, and erythrocytes containing hemoglobin F (fetal
hemoglobin) and ovalocytes are resistant to P. falciparum. In hyperendemic areas,
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newborns rarely become ill with malaria, in part because of passive maternal antibody
and high levels of fetal hemoglobin. Children 3 months to 2-5 years of age have little
specific immunity to malaria species and therefore suffer yearly attacks of debilitating
and potentially fatal disease. Immunity is subsequently acquired, and severe cases of
malaria become less common. Severe disease may occur during pregnancy,
particularly 1st pregnancies or after extended residence outside the endemic region. In
general, extracellular Plasmodium organisms are targeted by antibody, whereas
intracellular organisms are targeted by cellular defenses such as T lymphocytes,
macrophages, polymorphonuclear leukocytes, and the spleen.6
2.5 Clinical Manifestation
Children and adults are asymptomatic during the initial phase of infection, the
incubation period of malaria infection. The usual incubation periods are 9-14 days for
P. falciparum, 12-17 days for P. vivax, 16-18 days for P. ovale, and 18-40 days for P.
malariae. The incubation period can be as long as 6-12 mo for P. vivax and can also be
prolonged for patients with partial immunity or incomplete chemoprophylaxis. A
prodrome lasting 2-3 days is noted in some patients before parasites are detected in the
blood. Prodromal symptoms include headache, fatigue, anorexia, myalgia, slight fever,
and pain in the chest, abdomen, and joints.1
The classic presentation of malaria is seldom noted with other infectious
diseases and consists of paroxysms of fever alternating with periods of fatigue but
otherwise relative wellness. Febrile paroxysms are characterized by high fever, sweats,
and headache, as well as myalgia, back pain, abdominal pain, nausea, vomiting,
diarrhea, pallor, and jaundice. Paroxysms coincide with the rupture of schizonts that
occurs every 48 hr with P. vivax and P. ovale, resulting in fever spikes every other day.
Rupture of schizonts occurs every 72 hr with P. malariae, resulting in fever spikes
every 3rd or 4th day. Periodicity is less apparent with P. falciparum and mixed
infections and may not be apparent early on in infection, when parasite broods have
not yet synchronized. Patients with primary infection, such as travelers from
nonendemic regions, also may have irregular symptomatic episodes for 2-3 days before
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regular paroxysms begin. Children with malaria often lack typical paroxysms and have
nonspecific symptoms, including fever, headache, drowsiness, anorexia, nausea,
vomiting, and diarrhea.1
P. falciparum is the most severe form of malaria and is associated with higher
density parasitemia and a number of complications. The most common serious
complication is severe anemia, which also is associated with other malaria species.
Serious complications that appear unique to P. falciparum include cerebral malaria,
acute renal failure, respiratory distress from metabolic acidosis, algid malaria and
bleeding diatheses.
2.6 Diagnosis1
Prompt, accurate diagnosis of malaria is part of effective disease management.
All patients with suspected malaria should be treated on the basis of a confirmed
diagnosis by microscopy examination or RDT testing of a blood sample. Correct
diagnosis in malaria-endemic areas is particularly important for the most vulnerable
population groups, such as young children and non-immune populations, in whom
falciparum malaria can be rapidly fatal. High specificity will reduce unnecessary
treatment with antimalarial drugs and improve the diagnosis of other febrile illnesses
in all settings.
2.6.1 Suspected Malaria
The signs and symptoms of malaria are non-specific. Malaria is suspected
clinically primarily on the basis of fever or a history of fever. There is no combination
of signs or symptoms that reliably distinguishes malaria from other causes of fever;
diagnosis based only on clinical features has very low specificity and results in
overtreatment. Other possible causes of fever and whether alternative or additional
treatment is required must always be carefully considered. The focus of malaria
diagnosis should be to identify patients who truly have malaria, to guide rational use
of antimalarial medicines. In malaria-endemic areas, malaria should be suspected in
any patient presenting with a history of fever or temperature ≥ 37.5 °C and no other
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obvious cause. In areas in which malaria transmission is stable (or during the high-
transmission period of seasonal malaria), malaria should also be suspected in children
with palmar pallor or a haemoglobin concentration of < 8 g/dL. High-transmission
settings include many parts of sub-Saharan Africa and some parts of South East Asia.
In settings where the incidence of malaria is very low, parasitological diagnosis of all
cases of fever may result in considerable expenditure to detect only a few patients
with malaria. In these settings, health workers should be trained to identify patients
who may have been exposed to malaria (e.g. recent travel to a malaria-endemic area
without protective measures) and have fever or a history of fever with no other
obvious cause, before they conduct a parasitological test.
2.6.2 Parasitological Diagnosis
The benefit of parasitological diagnosis relies entirely on an appropriate
management response of health care providers. The two methods used routinely for
parasitological diagnosis of malaria are light microscopy and
immunochromatographic RDTs. The latter detect parasite-specific antigens or
enzymes that are either genus or species specific. The diagnosis of malaria is
established by identification of organisms on Giemsa-stained smears of peripheral
blood or by rapid immunochromatographic assay. Giemsa stain is superior to Wright
stain or Leishman stain. Both thick and thin blood smears should be examined. The
concentration of erythrocytes on a thick smear is 20-40 times that on a thin smear and
is used to quickly scan large numbers of erythrocytes. The thin smear allows for
positive identification of the malaria species and determination of the percentage of
infected erythrocytes and is useful in following the response to therapy.
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Identification of the species is best made by an experienced microscopist and
checked against color plates of the various Plasmodium species. Morphologically it is
impossible to distinguish P. knowlesi from P. malariae, so polymerase chain reaction
(PCR) detection by a reference lab or the CDC is required. Although P. falciparum is
most likely to be identified from blood just after a febrile paroxysm, the timing of the
smears is less important than their being obtained several times a day over a period of
3 successive days. A single negative blood smear does not exclude malaria. Most
symptomatic patients with malaria will have detectable parasites on thick blood
smears within 48 hr. For nonimmune persons, symptoms typically occur 1 to 2 days
before parasites are detectable on blood smear.
2.7 Treatment1
2.7.1 Uncomplicated P. falciparum Malaria
ACT is a combination of a rapidly acting artemisinin derivative with a longer-