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 914 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 worlds 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

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

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 2step 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.

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

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

hypergammaglobulinemia

anoxia;
and

the

polyclonal

activation

formation

of

resulting

immune

in

both

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,

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

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

obvious cause. In areas in which malaria transmission is stable (or during the hightransmission 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.

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 longeracting (more slowly eliminated) partner drug. The artemisinin component rapidly clears
parasites from the blood (reducing parasite numbers by a factor of approximately 10 000
in each 48-h asexual cycle) and is also active against the sexual stages of parasite that
mediate onward transmission to mosquitos. The longer-acting partner drug clears the
remaining parasites and provides protection against development of resistance to the

10

artemisinin derivative. Partner drugs with longer elimination half-lives also provide a
period of post-treatment prophylaxis. The five ACTs recommended for treatment of
uncomplicated P. falciparum malaria are:
artemether + lumefantrine
Body weight
(kg)
5
to
15
to
25
to

Dose (mg) of artemether + lumefantrine given

twice daily for 3 days
20 + 120
40 + 240
60 + 360

80 + 480

artesunate + amodiaquine
Body weight
(kg)

Artesunate + amodiaquine dose (mg) given

daily for 3 days

4.
59

25 + 67.5

to
18
to

100 + 270

50 + 135
200 + 540

artesunate + mefloquine
Body weight
(kg)
5
9to

Artesunate + mefloquine dose (mg) given daily

for 3 days
25 + 55

50 + 110

to
18
to

100 + 220
200 + 440

artesunate + SP
Body
Artesunate dose given
weight (kg) daily
for 3 days (mg)
5 to < 10

25 mg

Sulfadoxine /
pyrimethamine
dose (mg) given as a
single
250 / 12.5

10 to < 25 50 mg

500 / 25

25 to < 50 100 mg

1000 / 50

50

1500 / 75

200 mg

11

dihydroartemisinin + piperaquine.
Body
weight
(kg)
5
to
8
to
11
to
17
to
25
to
36
to
6
0

Dihydroartemisinin + piperaquine dose (mg)

given daily
for 3 days
20 + 160
30 + 240
40 + 320
60 + 480
80 + 640
120 + 960
160 + 1280
>
8

200 + 1600

2.7.2 Uncomplicated P. vivax Malaria

In areas with chloroquine-sensitive P. vivax

For chloroquine-sensitive vivax malaria, oral chloroquine at a total dose of 25 mg

base/kg bw is effective and well tolerated. Lower total doses are not recommended, as these
encourage the emergence of resistance. Chloroquine is given at an initial dose of 10
mg base/kg bw, followed by 10 mg/kg bw on the second day and 5 mg/kg bw on the
third day. In the past, the initial 10mg/kg bw dose was followed by 5 mg/kg bw at 6 h,
24 h and 48 h. As residual chloroquine suppresses the first relapse of tropical P. vivax
(which emerges about 3 weeks after onset of the primary illness), relapses begin to occur
5-7 weeks after treatment if radical curative treatment with primaquine is not given.
ACTs are highly effective in the treatment of vivax malaria, allowing simplification
(unification) of malaria treatment; i.e. all malaria infections can be treated with an ACT.
The exception is artesunate + SP, where resistance significantly compromises its
efficacy. Although good efficacy of artesunate + SP was reported in one study in
Afghanistan, in several other areas (such as South-East Asia) P. vivax has become
resistant to SP more rapidly than P. falciparum. The initial response to all ACTs is rapid in

12

vivax malaria, reflecting the high sensitivity to artemisinin derivatives, but, unless
primaquine is given, relapses commonly follow. The subsequent recurrence patterns differ,
reflecting the elimination kinetics of the partner drugs. Thus, recurrences, presumed
to be relapses, occur earlier after artemether + lumefantrine than after
dihydroartemisinin + piperaquine or artesunate + mefloquine because lumefantrine is
eliminated more rapidly than either mefloquine or piperaquine. A similar temporal
pattern of recurrence with each of the drugs is seen in the P. vivax infections that follow
up to one third of acute falciparum malaria infections in South-East Asia.

In areas with chloroquine-resistant P. vivax

ACTs containing piperaquine, mefloquine or lumefantrine are the recommended

treatment, although artesunate + amodiaquine may also be effective in some areas. In the
systematic review of ACTs for treating P. vivax malaria, dihydroartemisinin +
piperaquine provided a longer prophylactic effect than ACTs with shorter half-lives
(artemether + lumefantrine, artesunate + amodiaquine), with significantly fewer
recurrent parasitaemias during 9 weeks of follow-up (RR, 0.57; 95% CI, 0.40-0.82,
three trials, 1066 participants). The half-life of mefloquine is similar to that of
piperaquine, but use of dihydroartemisinin + piperaquine in P. vivax mono-infections has not
been compared directly in trials with use of artesunate + mefloquine.

2.7.3 Uncomplicated P. ovale, P. malariae and P. knowlesi

Resistance of P. ovale, P. malariae and P. knowlesi to antimalarial drugs is not
well characterized, and infections caused by these three species are generally
considered to be sensitive to chloroquine. In only one study, conducted in Indonesia,
was resistance to chloroquine reported in P. malariae. The blood stages of P. ovale, P.
malariae and P. knowlesi should therefore be treated with the standard regimen of
ACT or chloroquine, as for vivax malaria.

13

2.7.4 Mixed Malaria Infections

Mixed malaria infections are common in endemic areas. For example, in
Thailand, despite low levels of malaria transmission, 8% of patients with acute vivax
malaria also have P. falciparum infections, and one third of acute P. falciparum infections
are followed by a presumed relapse of vivax malaria (making vivax malaria the most
common complication of falciparum malaria).
Mixed infections are best detected by nucleic acid-based amplification techniques, such as
PCR. Cryptic P. falciparum infections in vivax malaria can be revealed in
approximately 75% of cases by RDTs based on the PfHRP2 antigen, but several RDTs
cannot detect mixed infection or have low sensitivity for detecting cryptic vivax
malaria. ACTs are effective against all malaria species and so are the treatment of
choice for mixed infections.

2.7.5 Primaquine for Preventing Relapse

To achieve radical cure (cure and prevention of relapse), relapses originating
from liver hypnozoites must be prevented by giving primaquine. The frequency and
pattern of relapses varies geographically, with relapse rates generally ranging
from 8% to 80%. Temperate long-latency P. vivax strains are still prevalent in many
areas. Recent evidence suggests that, in endemic areas where people are inoculated
frequently with P. vivax, a significant proportion of the population harbours dormant
but activatable hypnozoites. The exact mechanism of activation of dormant hypnozoites
is unclear. In most therapeutic assessments, primaquine has been given for 14 days.
Total doses of 3.5 mg base/kg bw (0.25 mg/kg bw per day) are required for temperate
strains and 7 mg base/kg bw (0.5 mg/kg bw per day) is needed for the tropical,
frequent-relapsing P. vivax prevalent in East Asia and Oceania. Primaquine causes
dose-limiting abdominal discomfort when taken on an empty stomach; it should
always be taken with food. Primaquine formulation: If available, administer scored
tablets containing 7.5 or 15 mg of primaquine. Smaller-dose tablets containing 2.5 and
5 mg base are available in some areas and facilitate accurate dosing in children. When

14

scored tablets are not available, 5 mg tablets can be used. Therapeutic dose: 0.25-0.5
mg/kg bw per day primaquine once a day for 14 days. Use of primaquine to prevent
relapse in high-transmission settings was not recommended previously, as the risk for
new infections was considered to outweigh any benefits of preventing relapse. This
may have been based on underestimates of the morbidity and mortality associated
with multiple relapses, particularly in young children.

2.7.6 Use of Antypyratic

In young children, high fevers are often associated with vomiting, regurgitation
of medication and seizures. They are thus treated with antipyretics and, if necessary,
fanning and tepid sponging. Antipyretics should be used if the core temperature
is > 38.5 C. Paracetamol (acetaminophen) at a dose of 15 mg/kg bw every 4 hr is
widely used; it is safe and well tolerated and can be given orally or as a suppository.
Ibuprofen (5 mg/kg bw) has been used successfully as an alternative in the treatment of
malaria and other childhood fevers, but, like aspirin and other non-steroidal antiinflammatory drugs, it is no longer recommended because of the risks of
gastrointestinal bleeding, renal impairment and Reyes syndrome.

2.7.7 Use of Antyemetics

Vomiting is common in acute malaria and may be severe. Parenteral
antimalarial treatment may therefore be required until oral administration is tolerated.
Then a full 3-day course of ACT should be given. Anti-emetics are potentially
sedative and may have neuropsychiatric adverse effects, which could mask or
confound the diagnosis of severe malaria. They should therefore be used with caution.
2.8 Severe Malaria8
2.8.1 Definition

15

For epidemiological purposes, severe falciparum malaria is defined as one or more of

the following, occurring in the absence of an identified alternative cause and in the
presence of P. falciparum asexual parasitaemia.
Impaired consciousness: A Glasgow coma score < 11 in adults or a Blantyre coma
score < 3 in children
Prostration: Generalized weakness so that the person is unable to sit, stand or walk
without assistance
Multiple convulsions: More than two episodes within 24 h
Acidosis: A base deficit of > 8 mEq/L or, if not available, a plasma bicarbonate level
of < 15 mmol/L or venous plasma lactate 5 mmol/L. Severe acidosis manifests
clinically as respiratory distress (rapid, deep, laboured breathing).
Hypoglycaemia: Blood or plasma glucose < 2.2 mmol/L (< 40 mg/dL)
Severe malarial anaemia: Haemoglobin concentration 5 g/dL or a haematocrit of
15% in children < 12 years of age (< 7 g/dL and < 20%, respectively, in adults) with a
parasite count > 10 000/L
Renal impairment: Plasma or serum creatinine > 265 mol/L (3 mg/dL) or blood
urea > 20 mmol/L
Jaundice: Plasma or serum bilirubin > 50 mol/L (3 mg/dL) with a parasite count >
100 000/ L
Pulmonary oedema: Radiologically confirmed or oxygen saturation < 92% on room
air with a respiratory rate > 30/min, often with chest indrawing and crepitations on
auscultation
Significant bleeding: Including recurrent or prolonged bleeding from the nose, gums
or venepuncture sites; haematemesis or melaena
Shock: Compensated shock is defined as capillary refill 3 s or temperature
gradient on leg (mid to proximal limb), but no hypotension. Decompensatedshock is

16

defined as systolic blood pressure < 70 mm Hg in children or< 80 mm Hg in adults,

with evidence of impaired perfusion (cool peripheries or prolonged capillary refill).
Hyperparasitaemia: P. falciparum parasitaemia > 10%. Severe vivax malaria is
defined as for falciparum malaria but with no parasite density thresholds.
Severe knowlesi malaria is defined as for falciparum malaria but with two differences:
P. knowlesi hyperparasitaemia: parasite density > 100 000/L
Jaundice and parasite density > 20 000/L.

2.8.2 Treatment of Severe Malaria

It is essential that full doses of effective parenteral (or rectal) antimalarial
treatment be given promptly in the initial treatment of severe malaria. This should be
followed by a full dose of effective ACT orally. Two classes of medicine are available
for parenteral treatment of severe malaria: artemisinin derivatives (artesunate or
artemether) and the cinchona alkaloids (quinine and quinidine). Parenteral artesunate
is the treatment of choice for all severe malaria. The largest randomized clinical trials
ever conducted on severe falciparum malaria showed a substantial reduction in
mortality with intravenous or intramuscular artesunate as compared with parenteral
quinine. The reduction in mortality was not associated with an increase in
neurological sequelae in artesunate-treated survivors. Furthermore, artesunate is
simpler and safer to use. Children weighing less than 20 kg should receive a higher
parenteral dose of artesunate (3 mg/kg/dose) than larger children and adults (2.4
mg/kg/dose) to ensure equivalent drug exposure

2.8.3 Blood Transfusion

Severe malaria is associated with rapid development of anaemia, as infected,
once infected and uninfected erythrocytes are haemolysed and/or removed from the
circulation by the spleen. Ideally, fresh, cross-matched blood should be transfused;

17

however, in most settings, cross-matched virus-free blood is in short supply. As for

fluid resuscitation, there are not enough studies to make strong evidence-based
recommendations on the indications for transfusion; the recommendations given here
are based on expert opinion. In high-transmission settings, blood transfusion is
generally recommended for children with a haemoglobin level of < 5 g/100 mL
(haematocrit < 15%). In low-transmission settings, a threshold of 20% (haemoglobin7
g/100 mL) is recommended. These general recommendations must, however, be
adapted to the individual, as the pathological consequences of rapid development of
anaemia are worse than those of chronic or acute anaemia when there has been
adaptation and a compensatory right shift in the oxygen dissociation curve.3

2.9 Complication9

Severe malarial anemia (hemoglobin level less than 5 g/dL) is the most common
severe complication of malaria in children and is the leading cause of anemia leading to
hospital admission in African children. Anemia is associated with hemolysis, but
removal of infected erythrocytes by the spleen and impairment of erythropoiesis likely
play a greater role than hemolysis in the pathogenesis of severe malarial anemia. The
primary treatment for severe malarial anemia is blood transfusion. With appropriate and
timely treatment, severe malarial anemia usually has a relatively low mortality (~1%).

Cerebral malaria is defined as the presence of coma in a child with P. falciparum

parasitemia and an absence of other reasons for coma. Children with altered mental
status who are not in coma fall into the larger category of impaired consciousness.
Cerebral malaria is most common in children in areas of midlevel transmission and in
adolescents or adults in areas of very low transmission. It is less frequently seen in areas
of very high transmission. Cerebral malaria often develops after the patient has been ill
for several days but may develop precipitously. Cerebral malaria is associated with a
fatality rate of 20-40% and is associated with long-term cognitive impairment in

18

children. Repeated seizures are frequent in children with cerebral malaria.

Hypoglycemia is common, but children with true cerebral malaria fail to arouse from
coma even after receiving a dextrose infusion that normalizes their glucose level.
Physical findings may be normal or may include high fever, seizures, muscular
twitching, rhythmic movement of the head or extremities, contracted or unequal pupils,
retinal hemorrhages, hemiplegia, absent or exaggerated deep tendon reflexes, and a
positive Babinski sign. Lumbar puncture reveals increased pressure and cerebrospinal
fluid protein with no pleocytosis and normal glucose and protein concentrations.
Treatment of cerebral malaria other than antimalarial medications is largely supportive
and includes evaluation of and treatment of seizures and hypoglycemia. Although
increased intracranial pressure has been documented in some children with cerebral
malaria, treatment with mannitol and corticosteroids has not improved outcomes in these
children.

Respiratory distress is a poor prognostic indicator in severe malaria and appears to be

due to metabolic acidosis rather than intrinsic pulmonary disease. To date, no successful
interventions for treatment of metabolic acidosis in children with severe malaria have
been described, but trials of dichloroacetate treatment and fluid expansion are ongoing.

Seizures are a common complication of severe malaria, particularly cerebral malaria.

Benzodiazepines are first-line therapy for seizures, and intrarectal diazepam has been
used successfully in children with malaria and seizures. Many seizures resolve with a
single dose of diazepam. For persistent seizures, phenobarbital or phenytoin are the
standard medications used. Phenytoin may be preferred for seizure treatment,
particularly in hospitals or clinics where ventilatory support is not available. However,
no comparative trials of the 2 drugs have been performed, and phenytoin is considerably
more expensive than phenobarbital. There are currently no drugs recommended for
seizure prophylaxis in children with severe malaria. Phenobarbital prophylaxis

19

decreased seizure activity but increased mortality in 1 major study of children with
severe malaria, probably because of the respiratory depression associated with
phenobarbital that may have been exacerbated by benzodiazepine therapy.

Hypoglycemia is a complication of malaria that is more common in children, pregnant

women, and patients receiving quinine therapy. Patients may have a decreased level of
consciousness that can be confused with cerebral malaria. Any child with impaired
consciousness and malaria should have a glucose level checked, and if glucometers are
not available, an empirical bolus of dextrose should be given. Hypoglycemia is
associated with increased mortality and neurologic sequelae.

Circulatory collapse (algid malaria) is a rare complication that manifests as

hypotension, hypothermia, rapid weak pulse, shallow breathing, pallor, and vascular
collapse. Death may occur within hours. Severe malaria is occasionally accompanied by
bacteremia, which may have been the cause of some of the cases previously referred to
as algid malaria. Any child with severe malaria and hypotension should have a blood
culture obtained and be treated empirically for bacterial sepsis.

Long-term cognitive impairment occurs in 25% of children with cerebral malaria and
also occurs in children with repeated episodes of uncomplicated disease. Prevention of
attacks in these children significantly improves educational attainment.

Tropical splenomegaly syndrome is a chronic complication of P. falciparum malaria in

which massive splenomegaly persists after treatment of acute infection. The syndrome is
characterized by marked splenomegaly, hepatomegaly, anemia, and an elevated IgM

20

level. Tropical splenomegaly syndrome is thought to be caused by an impaired immune

response to P. falciparum antigens. Prolonged antimalarial prophylaxis (for at least
several years) is required to treat this syndrome if the child remains in a malaria endemic
area. Spleen size gradually regresses on antimalarial prophylaxis but often increases
again if prophylaxis is stopped.

Other complications in children include jaundice, which is associated with a worse

outcome, and prostration. Prostration is defined as the inability to sit, stand, or eat
without support, in the absence of impaired consciousness. Prostration also has been
associated with increased mortality in some studies, but the pathophysiology of this
process is not well understood. Uncommon complications include hemoglobinuria,
abnormal bleeding, pulmonary edema, and renal failure. These are uncommon
complications in children with severe malaria and are more common in adults,
particularly pulmonary edema and renal failure.

21

CHAPTER 3
CASE REPORT
3.1.

Case
SS, 5 years and 11 month girl, BW 14 kg, BH 104 cm admitted to emergency

room in H. Adam Malik General Hospital Medan on September 14th 2015 at 06.45 pm
with a complain fever.
3.2 History of Disease
SS was admitted to Haji Adam Malik General Hospital Medan complaining of
fever since +/- 2 weeks prior to admission to the hospital. Body temperature is
unstable, sometimes high grade fever which was reduced with antipyretics. Patient
experienced shivering while having high fever. Convulsions were not found. Patient
reported vomiting since 2 weeks. Vomiting occurred after taking medicine. The
contents were food and drink that she ate. Patient also reported headache, myalgia
during fever. Cough and coryza was found in this 1 week. Her parents realized that
patient was pallor since 1 week. History travel to endemic region was denied by her
parents, but she lives in Langkat.
Previous illness: Referred from RS Pirngadi and diagnosed with Plasmodium vivax
malaria.

22

History of medication: Novalgin

History of family: None
History of parents medication: None
History of Pregnancy: The age of mother was not remembered during pregnancy.
The gestation was normal, 36 weeks.
History of Birth: Birth was assisted by midwife. The patient was born pervaginal and
cried immediately after birth. Body weight at birth was 3500 gram, body length at
birth was 50 cm.
History of feeding: Unclear

History of immunization: Complete immunization

History of growth and development: The patients mother reported that SS grew
normally. SS had developed talking, crawling, and walking skills on time.

Physical Examination:
Present Status: Level of consciousness: Alert, Compos mentis. Blood pressure:
100/40 mmHg, Respiratory rate: 24 x/i, regular. Pulse : 140 x/i reguler, Body
temperature: 38,3C, Body weight : 14 kg, Body height : 104 cm. BW/A: 70%, BH/A:
96%, BW/BH: 73,6%, anemic (+), ikteric (-), dyspnea (-), cyanotic (-), edema (-).
Localized Status
Head: Eye: Eye light reflect +/+, pale conjunctiva palpebral inferior +/+,
Ear/nose/mouth : Within normal range.
Neck: Jugular Vein Pressure : R-2 cmH2O
Thorax: Symetrical fusiformis, Retractions (-), Respiratory Rate : 24 x/i, regular,
ronchi -/-. Heart rate : 140 x/i, regular, murmur (-)

23

Abdomen: Soepel, Peristaltic (+) normal, Hepar: palpable 2 cm BAC, Lien: palpable
S II
Extremities: Pulse: 140x/i, regular, adequate pressure and volume, warm, CRT < 3,
Pale (+), Pretibial edema (-), Blood pressure: 100/50 mmHg.
Laboratory Findings:
14th September 2015
Complete blood count:
Test

Res

Unit

ult
Hemoglob

5.60

al
g%

in
Erythrocyt

Thromboc

1.76
6.11
164

yte
Hematocry
te

12.014.4

e
Leucocyte

Refer

14.9

106/m

4.75-

m3

4.85

103/m

4.5-

m3

11.0

103/m

150-

m3

450

36-

42

Eosinophil

1.10

1-6

Basophil

0.20

0-1

37-

0
Neutrophil

63.4
0

Lymphocy
te

27.0

80
%

2040

Monocyte

8.30

2-8

Absolute

3.67

103/

2.7-

6.5

neutrophil

24

Absolute

1.65

103/

1.5-

3.7

103/

0.2-

0.4

103/

0-0.1

lymphocyt
e
Absolute

0.51

monocyte
Absolute

0.01

basophil

MCV

64.7

Fl

0
MCH

31.8

87
Pg

0
MCHC

37.6

g%
%

0
9.50

3335

27.1

MPV

2531

0
RDW

75-

11.614.8

fL

7.010.2

PCT

0.16

PDW

11.3

fL

Electrolyte
Test

Resul

Unit

Referal

mEq/

135-155

t
Natrium

138

L
Kalium

4.1

mEq/

3.6-5.5

L
Chlorid
e

105

mEq/
L

96-106

25

Differential Diagnosis: - Thypoid fever

- Viral infection : influenza

Working Diagnosis : Malaria

Therapy:
-

IVFD D5% NaCl 0,45% 50 gtt/i micro

Diet MB 1200 kkal with 26 gram protein

Paracetamol syr 3 x cth 11/2

Further Investigation Plan:

-

Thick and thin blood smears

LFT

RFT

Urinalysis

26

Follow Up:
14th September 2015
S
O
A
o
Fever (+)
Sens: Alert, T: 38,3 C, BW: Malaria+
14 kg, BH: 104 cm

anaemia

P
IVFD D5% NaCl 0,45% 30
gtt/i,

Head: eye reflect +/+, isocor,

DHP tablet 1x1 for 3 days

pale conj. palpebral inferior

(Day 1)

+/+, ear/nose/mouth: normal

Diet MB 1200 kcal with 28

Neck: JVP R-2 cmH2O

gram protein

Thorax: Symetris fusiformis,

Planned to check RDT, thin

retraction (-), HR: 140x/i,

blood smears, G6PD, LFT,

regular, murmur (-), RR: 24

RFT,

x/i, Ronchi -/-

culture,

Abdomen: Soepel, Normal

Transfusion (11-5,6) x 4 x

peristaltic, Hepar : palpable

14 = 300

Urinalysis,
and

Urine
PRC

27

2 cm BAC, Lien : palpable S

Kemampuan : 5 x 14 = 75

II

cc/12 hours

Extremities: Pulse: 140 x/i,

regular, adequate pressure

Result ( 07.00 pm)

and volume, warm, CRT <

Clinical Pathology

3, pale (+), pretibial edema

Hematologi

(-)

Malaria (+)

Others: Normal
Morfology
Erythrocytes: Ring form (+),
Trophozoite (+)
th

15 September 2015
S
O
A
o
Fever (-),
Sens: Alert, T: 36,8 C, BW: Malaria+
14 kg, BH: 104cm

anaemia

P
IVFD D5% NaCl 0,45% 50
gtt/i

Head: eye reflect +/+, isocor,

DHP tablet 1x1 for 3 days

pale conj. palpebral inferior

(Day 2)

+/+, ear/nose/mouth: normal

Diet MB 1200 kcal with 28

Neck: JVP R-2 cmH2O

gram protein

Thorax: Symetris fusiformis,

PRC Tranfusion 75 cc (Bag

retraction (-), HR: 120 x/i,

1)

regular, murmur (-), RR: 24

x/i, regular, Ronchi -/Abdomen: Soepel, Normal
peristaltic, Hepar: palpable 2
cm BAC, Lien : palpable S
II
Extremities: Pulse: 120 x/i,
regular, adequate pressure
and volume, warm, CRT <
3, pale (+), pretibial edema
(-)

28

Others: Normal
16 September 2015
S
O
A
Fever (-)
Sens: Alert, T: 36,8 oC, BW: Malaria+anaemi
th

14 kg, BH: 104 cm

P
IVFD D5% NaCl 0,45% 50
gtt/i

Head: eye reflect +/+, isocor,

DHP tablet 1x1 for 3 days

pale conj. palpebral inferior

(Day 3)

Diet MB 1200 kcal with 28

Neck: JVP R-2 cmH2O

gram protein

Thorax: Symetris fusiformis,

PRC Tranfusion 75 cc (Bag

retraction (-), HR: 110 x/i,

2)

/+, ear/nose/mouth: normal

murmur (-), RR: 24 x/i,

Ronchi -/Abdomen: Soepel, Normal
peristaltic, Hepar: palpable 2
cm BAC, Lien : palpable S
II

Clinical Pathology

Extremities: Pulse: 110 x/i,

(11.42 AM)

regular, warm, CRT < 3,

Urinalysis

pretibial edema (-)

Complete Urine Morphology

Color : Yellow
Glocose : (-)
Bilirubin : (-)
Keton : (-)
Berat Jenis : 1.015
pH : 6
Urobilinogen : (-)
Nitrit : (-)
Leucocyte : (+)
Blood : (-)
Urine Sediment

29

Erythrocyte : 0-1
Leucocyte : 1-2
Epytel : 0-1
Casts : (-)
Crystal : (-)
th

17 September 21015
S
O
A
o
Fever (-)
Sens: Alert, T: 36,8 C, BW: Malaria+
14 kg, BH: 104 cm

anaemia

P
IVFD D5% NaCl 0,45% 50
gtt/i

Head: eye reflect +/+, isocor,

Diet MB 1200 kcal with 28

pale conj. palpebral inferior

gram protein

/-, ear/nose/mouth: normal

PRC Tranfusion 75 cc (Bag

Neck: JVP R-2 cmH2O

3)

Thorax: Symetris fusiformis,

Primakuin tablet 1 x 1/4 for

retraction (-), HR: 94 x/i,

14 days (Day 1)

murmur (-), RR: 20 x/i,

Ronchi -/-

G6PD Deficiency : (-)

Abdomen: Soepel, Normal

peristaltic, Hepar: palpable 2
cm BAC, Lien : palpable S
II
Extremities: Pulse: 94 x/i,
regular, warm, CRT < 3,
pretibial edema (-)
18th September 2015
S
O

30

Fever (-)

Sens: Alert, T: 36,6 oC, BW: Malaria

IVFD D5% NaCl 0,45% 50

14 kg, BH: 104 cm

gtt/i

Head: eye reflect +/+, isocor,

Diet MB 1200 kcal with 28

pale conj. palpebral inferior

gram protein

/-, ear/nose/mouth: normal

Primakuin tablet 1 x 1/4 for

Neck: JVP R-2 cmH2O

14 days (Day 2)

Thorax: Symetris fusiformis,

PRC Tranfusion 75 cc (Bag

retraction (-), HR: 100 x/i,

4)

regular, murmur (-), RR: 22

x/i, regular, ronchi -/-

Check

Complete

Blood

Abdomen: Soepel, Normal

Count after transfusion

peristaltic, Hepar: palpable 2

cm BAC, Lien : palpable S

Complete

II

(09.11)

Extremities: Pulse: 110 x/i,

Test

Blood

Count
Result

regular, warm, CRT < 3,

Hemoglobin

10.40

pretibial edema (-)

Erythrocyte

2.70x103

Leucocyte

5.40x103

Thrombocyte

275x103

Hematocryte

23.20

Eosinophil

7.40

Basophil

0.600

Neutrophil

35.90

Lymphocyte

49.40

Monocyte

6.70

Absolute

3.67

neutrophil
Absolute

1.65

lymphocyte
Absolute

2.67

monocyte

31

19th September 2015

S
O
A
Fever (-)
Sens: Alert, T: 36,8 oC, BW: Malaria

Absolute

0.03

basophyl
MCV

85.90

MCH

38.50

MCHC

44.80

RDW

22.40

MPV

10.20

PCT

0.28

PDW

12.4

P
IVFD D5% NaCl 0,45% 50

14 kg, BH: 104 cm

gtt/i

Head: eye reflect +/+, isocor,

Diet MB 1200 kcal with 28

pale conj. palpebral inferior

gram protein

/-, ear/nose/mouth: normal

Primakuin tablet 1 x 1/4 for

Neck: JVP R-2 cmH2O

14 days (Day 3)

Thorax: Symetris fusiformis,

retraction (-), HR: 100 x/i,
murmur (-), RR: 24 x/i,

Ronchi -/Abdomen: Soepel, Normal

peristaltic, Hepar: palpable 2
cm BAC, Lien : palpable S
II
Extremities: Pulse: 100 x/i,
regular, warm, CRT < 3,
pretibial edema (-)
20th September 2015
S
O
A
o
Fever (-)
Sens: Alert, T: 36,6 C, BW: Malaria
14 kg, BH: 104 cm

P
IVFD D5% NaCl 0,45% 50
gtt/i

32

Head: eye reflect +/+, isocor,

Diet MB 1200 kcal with 28

pale conj. palpebral inferior

gram protein

/-, ear/nose/mouth: normal

Primakuin tablet 1 x 1/4 for

Neck: JVP R-2 cmH2O

14 days (Day 4)

Thorax: Symetris fusiformis,

retraction (-), HR: 84 x/i,
murmur (-), RR: 20 x/i,
Ronchi -/Abdomen: Soepel, Normal
peristaltic, Hepar: palpable 2
cm BAC, Lien : palpable S
II
Extremities: Pulse: 84 x/i,
regular, warm, CRT < 3,
pretibial edema (-)

33

CHAPTER 4
DISCUSSION AND SUMMARY
4.1.

Discussion
Malaria is one of endemic disease in tropical country or subtropic country. Malaria is a

health problem in Mexico, Caribia, Central America, Africa, India, South East, and Indo Cina. It
is estimated the prevalence of malaria up to 160-400 million cases. In Indonesia, malaria is still
found in some provinces. Plasmodium falciparum and Plasmodium vivax are the most species in
Indonesia. Children are one of most vulnerable groups affected by malaria. In this case, the
patient is children, 5 years, 11 month and has Plasmodium vivax malaria.
According to Pemprov (2010), in North Sumatera there are some endemic regions of
malaria, such as: Kabupaten Langkat, Deli Serdang, Labuhan Batu, Serdang Bedagai, Asahan,
Samosir, Tapanuli Tengah, Tapanuli Utara, Tapanuli Selatan, Mandailing Natal, Nias, Batu Bara,
Padang Lawas, Padang Lawas Utara dan Kabupaten Labuhan Batu Utara. In this case, the patient
is from Langkat.
In this case, the patient has a history of fever with unstable temperature. Sometimes high
grade fever and reduced with antipyretics. Patient also complain shiverring while high fever.
Patient also reported headache, myalgia if she had fever. Cough and coryza was found in this 1

34

week. Her parents realized that patient was pallor since 1 week. From physical examination,
found that patient has hepatosplenomegaly. Patient didnt have a travel to endemic area, but she
lives in endemic area, that is Langkat. The history, clinical manifestation and physical
examination are suitable with the theory. Based on Behrman, R.E (2004), children with malaria
often have special clinical features that differ from those of adults. In children older than 2
months of age, symptoms of malaria vary widely from low-grade fever and headache to a
temperature greater than 104F with headache, drowsiness, anorexia, nausea, vomiting, diarrhea,
pallor, cyanosis, splenomegaly, hepatomegaly, or any combination of these manifestations.
Anemia is one of important pathologic processes have been identified in patients with
malaria. Anemia is caused by hemolysis, sequestration of erythrocytes in the spleen and other
organs, and inhibition of erythropoiesis by TNFa. In this case, patient has an anemia with
Hemoglobin count is 5.60 gr/dl.
All episodes of malaria should be treated with at least two effective antimalarial
medicines with different mechanism of action that is by using Artemisinin base Combination
treatment (ACT) combined with Primaquine. ACT which available in Indonesia are: Artesunate
+ Amodiaquine ( AS+AQ) , Artemether + Lumefantrine (AL), and Dihydroartemisinin+Piperaquine (DHP ).11 Based on a randomized study by Pasaribu et al (2013), Artesunate +
Amodiaquine and Dihydroartemisinin-+Piperaquine combined with primaquine were effective
for blood stage parasite clearance of uncomplicated P. vivax. Both treatment were safe, but
Dihydroartemisinin-+Piperaquine was better tolerated. Patient treated with Dihydroartemisinin+Piperaquine combined with Piperaquine.
Primaquine has oxidative side effect causing intravascular hemolysis in populations in
whom glucose-6-phosphate dehydrogenase (G6PD) deficiency. So, before receive Primaquine,
patient should be tested glucose-6-phosphate dehydrogenase (G6PD) deficiency. In this case,
patient was screened for (G6PD) deficiency and the result was negative. So, the patient receive
Primaquine teraphy for 14 days.
4.2.

Summary
So the summary is, SS, 5 years and 11 months girl, that weighted 14 kg and heighted 104

cm, from emergency unit in H. Adam Malik General Hospital Medan on September 14 th 2015 at
06.45 PM develops fever since 2 weeks ago. Patient experienced shivering during high fever.

35

Patient reported vomiting since 2 weeks. Vomiting recurred after taking medicine. The contents
were food and drink that she ate. Patient also reported headache, myalgia if she had fever. She
lives in Langkat. She is diagnosed with Plasmodium vivax malaria. Patients was treated with
DHP for 3 days and Primaquine for 14 days.

REFERENCES
1. World Health Organization. Guidelines for The Treatment of Malaria. 3 rd Edition. 2015.
Available from: http://www.who.int/about/licensing/copyright_form/en/index.html. Accesed
on 11 September 2015.
2. Behrman, R.E; Kliegman, R.M; Jenson, H; Saunders, W.B. Nelson Textbook of Pediatrics.
17th Edition. Elsevier; 2004.
3. World Health Organization. World Malaria Report 2014. Available from:
http://www.who.int/malaria/publications/world_malaria_report_2014/en. Accesed
on 12 September 2015
4. Centers for Disease Control and Prevention. Malaria. 2012. Available from:
http://www.cdc.gov/malaria. Accesed on 12 September 2015.
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Malaria di Indonesia. 2008
6. Harijanto, P.N. 2000. Malaria, Epidemiologi, Patogenesis, Manifestasi klinis dan
Penanganan. Penerbit Buku Kedokteran EGC: Jakarta.
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tropical medicine and emerging infectious diseases. Edisi ke-8. Philadelphia:
Saunders; 2000.h.614-41

36

8. H.P. Paul, 2009. Malaria. In: W.Sudoyo, Setiyohadi B., Alwi I., Simadibrata M.,
Setiati . ed. Buku Ajar Penyakit Dalam. InternaPublishing, Jakarta, 2813 2825.
9. OBrien D., et al, 2001. Fever In Returned Travellers : Reviews of Hospital
Admissions For a 3- years Period. Clinical Infectious Diseases 33 : 603 609.
10. Depkes RA, 2011. Epideomologi Malaria Di Indonesia. Profil Kesehatan Indonesia
2011. Available from : http://www.depkes.go.id/pdf.