Malaria Case Presentation

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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-

acting (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

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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) Dose (mg) of artemether + lumefantrine given twice daily for 3 days

5 to

20 + 120

15 to

40 + 240

25 to

60 + 360

≥

80 + 480

• artesunate + amodiaquine

Body weight (kg) Artesunate + amodiaquine dose (mg) given daily for 3 days

4.5

25 + 67.5

9 to

50 + 135

18 to

100 + 270

≥

200 + 540

• artesunate + mefloquine

Body weight (kg) Artesunate + mefloquine dose (mg) given daily for 3 days

5 to

25 + 55

9 to

50 + 110

18 to

100 + 220

≥

200 + 440

• artesunate + SP

Bodyweight (kg)

Artesunate dose given dailyfor 3 days (mg)

Sulfadoxine / pyrimethaminedose (mg) given as a singledose on day 1

5 to < 10 25 mg 250 / 12.5

10 to < 25 50 mg 500 / 25

25 to < 50 100 mg 1000 / 50

≥ 50 200 mg 1500 / 75

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• dihydroartemisinin + piperaquine.

Body weight (kg)

Dihydroartemisinin + piperaquine dose (mg) given daily

for 3 days5 to

20 + 160

8 to

30 + 240

11 to

40 + 320

17 to

60 + 480

25 to

80 + 640

36 to

120 + 960

60

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

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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.

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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.

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When 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 ºC. 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 anti-

inflammatory drugs, it is no longer recommended because of the risks of

gastrointestinal bleeding, renal impairment and Reye’s 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

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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/μL

• Renal impairment: Plasma or serum creatinine > 265 μmol/L (3 mg/dL) or blood

urea > 20 mmol/L

• Jaundice: Plasma or serum bilirubin > 50 μmol/L (3 mg/dL) with a parasite count >

100 000/ μL

• 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

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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/µL

• Jaundice and parasite density > 20 000/µL.

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;

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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

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

Hypoglycemia is common, but children with true cerebral malaria fail to arouse from

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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

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.

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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

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

20

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.

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.

22

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 patient’s 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: 38,3°C, 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 (-)

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.

23

Laboratory Findings:

14th September 2015

Complete blood count:

Test Res

ult

Unit Refer

al

Hemoglob

in

5.60 g% 12.0-

14.4

Erythrocyt

e

1.76 106/

mm3

4.75-

4.85

Leucocyte 6.11 103/

mm3

4.5-

11.0

Thromboc

yte

164 103/

mm3

150-

450

Hematocry

te

14.9

0

% 36-

42

Eosinophil 1.10 % 1-6

Basophil 0.20

0

% 0-1

Neutrophil 63.4

0

% 37-

80

Lymphocy

te

27.0

0

% 20-

40

Monocyte 8.30 % 2-8

Absolute

neutrophil

3.67 103/

µL

2.7-

6.5

Absolute 1.65 103/ 1.5-

24

lymphocyt

e

µL 3.7

Absolute

monocyte

0.51 103/

µL

0.2-

0.4

Absolute

basophil

0.01 103/

µL

0-0.1

MCV 64.7

0

Fl 75-

87

MCH 31.8

0

Pg 25-

31

MCHC 37.6

0

g% 33-

35

RDW 27.1

0

% 11.6-

14.8

MPV 9.50 fL 7.0-

10.2

PCT 0.16 %

PDW 11.3 fL

Electrolyte

Test Resul

t

Unit Referal

Natrium 138 mEq/L 135-155

Kalium 4.1 mEq/L 3.6-5.5

Chloride 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 P

Fever (+) Sens: Alert, T: 38,3 oC, BW:

14 kg, BH: 104 cm

Head: eye reflect +/+, isocor,

pale conj. palpebral inferior

+/+, ear/nose/mouth: normal

Neck: JVP R-2 cmH2O

Thorax: Symetris fusiformis,

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

regular, murmur (-), RR: 24

x/i, Ronchi -/-

Abdomen: Soepel, Normal

peristaltic, Hepar : palpable

Malaria+

anaemia

IVFD D5% NaCl 0,45% 30

gtt/i,

DHP tablet 1x1 for 3 days

(Day 1)

Diet MB 1200 kcal with 28

gram protein

Planned to check RDT, thin

blood smears, G6PD, LFT,

RFT, Urinalysis, Urine

culture, and PRC

Transfusion (11-5,6) x 4 x

27

2 cm BAC, Lien : palpable S

II

Extremities: Pulse: 140 x/i,

regular, adequate pressure

and volume, warm, CRT <

3”, pale (+), pretibial edema

(-)

Others: Normal

14 = 300

Kemampuan : 5 x 14 = 75

cc/12 hours

Result ( 07.00 pm)

Clinical Pathology

Hematologi

Malaria (+)

Morfology

Erythrocytes: Ring form (+),

Trophozoite (+)

15th September 2015

S O A P

Fever (-), Sens: Alert, T: 36,8 oC, BW:

14 kg, BH: 104cm


pale conj. palpebral inferior

+/+, ear/nose/mouth: normal

Neck: JVP R-2 cmH2O


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


x/i, regular, Ronchi -/-


peristaltic, Hepar: palpable 2

cm BAC, Lien : palpable S

II


regular, adequate pressure

and volume, warm, CRT <

Malaria+

anaemia


gtt/i


(Day 2)


gram protein

PRC Tranfusion 75 cc (Bag

1)

28

3”, pale (+), pretibial edema

(-)

Others: Normal

16th September 2015

S O A P

Fever (-) Sens: Alert, T: 36,8 oC, BW:

14 kg, BH: 104 cm


pale conj. palpebral inferior +/+, ear/nose/mouth: normal

Neck: JVP R-2 cmH2O



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

Ronchi -/-




II


regular, warm, CRT < 3”,

pretibial edema (-)

Malaria+anaemia IVFD D5% NaCl 0,45% 50

gtt/i


(Day 3)


gram protein


2)

Clinical Pathology

(11.42 AM)

Urinalysis

Complete Urine Morphology

Color : Yellow

Glocose : (-)

Bilirubin : (-)

Keton : (-)

Berat Jenis : 1.015

pH : 6

Urobilinogen : (-)

Nitrit : (-)

Leucocyte : (+)

29

Blood : (-)

Urine Sediment

Erythrocyte : 0-1

Leucocyte : 1-2

Epytel : 0-1

Casts : (-)

Crystal : (-)

17th September 21015

S O A P


14 kg, BH: 104 cm


pale conj. palpebral inferior -/-, ear/nose/mouth: normal

Neck: JVP R-2 cmH2O




Ronchi -/-




II



pretibial edema (-)

Malaria+

anaemia


gtt/i


gram protein


3)

Primakuin tablet 1 x 1/4 for

14 days (Day 1)

G6PD Deficiency : (-)

18th September 2015

S O A P

Fever (-) Sens: Alert, T: 36,6 oC, BW: Malaria IVFD D5% NaCl 0,45% 50

30

14 kg, BH: 104 cm



Neck: JVP R-2 cmH2O




x/i, regular, ronchi -/-




II



pretibial edema (-)

gtt/i


gram protein


14 days (Day 2)


4)

Check Complete Blood

Count after transfusion

Complete Blood Count

(09.11)

Test Result

Hemoglobin 10.40

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

neutrophil

3.67

Absolute

lymphocyte

1.65

Absolute

monocyte

2.67

31

Absolute

basophyl

0.03

MCV 85.90

MCH 38.50

MCHC 44.80

RDW 22.40

MPV 10.20

PCT 0.28

PDW 12.4

19th September 2015

S O A P


14 kg, BH: 104 cm



Neck: JVP R-2 cmH2O




Ronchi -/-




II



pretibial edema (-)

Malaria IVFD D5% NaCl 0,45% 50

gtt/i


gram protein


14 days (Day 3)

\

20th September 2015

S O A P

32


14 kg, BH: 104 cm



Neck: JVP R-2 cmH2O




Ronchi -/-




II



pretibial edema (-)

Malaria IVFD D5% NaCl 0,45% 50

gtt/i


gram protein


14 days (Day 4)

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.

34

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

week. Her parents realized that patient was pallor since 1 week. From physical examination,

found that patient has hepatosplenomegaly. Patient didn’t 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 104°F 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

35

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.

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. 3rd 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.

5. Departemen Kesehatan Republik Indonesia. Pedoman Penatalaksanaan Kasus

Malaria di Indonesia. 2008

6. Harijanto, P.N. 2000. Malaria, Epidemiologi, Patogenesis, Manifestasi klinis dan

Penanganan. Penerbit Buku Kedokteran EGC: Jakarta.

http://www.cdc.gov/malaria

36

7. Taylor TE, Strickland GT. Malaria. Dalam: Strickland GT, penyunting. Hunter’s

tropical medicine and emerging infectious diseases. Edisi ke-8. Philadelphia:

Saunders; 2000.h.614-41

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. O’Brien 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.

Documents

Malaria Case Presentation