CHAPTER 1

INTRODUCTION

1.1 Background

The estimated worldwide incidence of malaria is greater than 350–500 million clinical

malaria episodes per year, with more than 1 million deaths annually, most of which occur in

children younger than 5 years. Almost all deaths are due to P. falciparum, with more than

80% occurring in sub-Saharan Africa. Prior to the 1950s, malaria was endemic throughout

the southeastern United States. During the late 1940s, a combination of improved housing

and socioeconomic conditions, water management, vector-control efforts, and case

management was successful at interrupting malaria transmission in the United States. In the

United States today, most cases occur in persons who have traveled to or are emigrating from

malarious areas, although transmission also can occur congenitally or through blood

transfusion or organ transplantation. Anopheline vectors are still present in most areas of the

United States, and, occasionally, localized outbreaks of malaria occur because of

transmission from imported human cases.

Malaria is a major health problem in Africa, Asia, Central America, Oceania, and

South America. About 40% of the world's population lives in areas where malaria is

common. Approximately 300-500 million cases of malaria occur every year, and 1-2 million

deaths occur, most of them in young children. People of all races are affected by malaria,

with some exceptions. People of West African origin who do not have the Duffy blood group

are not susceptible to P vivax malaria.

Malaria is an ancient disease and references to what was almost certainly malaria

occur in a Chinese document from about 2700 BC, clay tablets from Mesopotamia from 2000

BC, Egyptian papyri from 1570 BC and Hindu texts as far back as the sixth century BC. Such

historical records must be regarded with caution but moving into later centuries we are

beginning to step onto firmer ground. The early Greeks, including Homer in about 850 BC,

Empedocles of Agrigentum in about 550 BC and Hippocrates in about 400 BC, were well

aware of the characteristic poor health, malarial fevers and enlarged spleens seen in people

living in marshy places.

Malaria may be a common illness in areas where it is transmitted and therefore the

diagnosis of malaria should routinely be considered for any febrile person who has traveled to

an area with known malaria transmission in the past several months preceding symptom

onset.

Symptoms of malaria are generally non-specific and most commonly consist of fever,

malaise, weakness, gastrointestinal complaints (nausea, vomiting, diarrhea), neurologic

complaints (dizziness, confusion, disorientation, coma), headache, back pain, myalgia, chills,

and/or cough. The diagnosis of malaria should also be considered in any person with fever of

unknown origin regardless of travel history.

In all settings, clinical suspicion of malaria should be confirmed with a parasitological

diagnosis. However, in settings where parasitological diagnosis is not possible, the decision

to provide antimalarial treatment must be based on the prior probability of the illness being

malaria. Other possible causes of fever and need for alternative treatment must always be

carefully considered.

Since the advent of chloroquine in the 1930s, treatment of fever with antimalarial

drugs, without confirmatory diagnosis, has been the accepted standard of practice in many

malaria-endemic areas, especially in Africa. However, the clinical presentation of malaria

overlaps with other common illnesses, and attempts to develop clinical scoring systems of

predictive value have proved unsuccessful. Presumptive treatment has therefore resulted in

overuse of antimalarial drugs, increasing drug resistance, and, importantly, failure to treat

alternative causes of fever. WHO now recommends that parasitological confi rmation by

microscopy or rapid diagnostic test is obtained in all patients with suspected malaria before

the start of treatment

After malaria parasites are detected on a blood smear, the parasite density should then

be estimated. The parasite density can be estimated by looking at a monolayer of red blood

cells (RBCs) on the thin smear using the oil immersion objective at 100x. The slide should be

examined where the RBCs are more or less touching (approximately 400 RBCs per field).

The parasite density can then be estimated from the percentage of infected RBCs, after

counting 500 to 2000 RBCs.

Rapid diagnostic tests (RDTs) have been developed that can detect antigens derived

from malaria parasites. Such tests most often use a dipstick or cassette format, and provide

results in 2 to 15 minutes. Rapid diagnostic tests offer a useful alternative to microscopy in

situations where reliable microscopic diagnosis is not immediately available.

Parasite nucleic acid detection using polymerase chain reaction (PCR) is more

sensitive and specific than microscopy but can be performed only in reference laboratories

and should be reserved for specific instances (e.g., back-up or confirmation of microscopy).

Serologic tests, also performed in reference laboratories, can be used to assess past malaria

experience but not current infection by malaria parasites.

2.2 Objective

This paper is done in order to complete the task in following the doctor’s professional

education program in the department of pediatrics. In addition, providing knowledge to the

author and readers about malaria.

CHAPTER 2

LITERATURE REVIEW

2.1 Description of the pathogen

Four species of malarial parasites commonly infect humans, Plasmodium falciparum,

Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae. P. falciparum is the most

lethal and the most drug resistant. From an evolutionary standpoint, P. falciparum is the

Plasmodium species most recently acquired by humans; by genetic analysis, it is related most

closely to malarial species in birds. Of the human species of Plasmodium, P. vivax was the

most widely distributed geographically and best adapted to survive in temperate climates.

However, successful mosquito eradication programs in the United States and Europe

essentially eliminated P. vivax from these regions. P. falciparum is the most prevalent in sub-

Saharan Africa. P. ovale mainly occurs in the western areas of sub-Saharan Africa.

Figure 1. Life Cycle of Malaria

Sporozoites are inoculated into humans by the bite of an Anopheles mosquito and

invade hepatic parenchymal cells within minutes. The parasites undergo asexual

multiplication, or schizogony, in this tissue phase of their lifecycle, also called exo-

erythrocyticschizogony. After a period of development and amplification (7 to 10 days for P.

falciparum, P. ovale, and P. vivax and 10 to 14 days for P. malariae), merozoites emerge to

invade erythrocytes and begin what will become the symptomatic phase of the illness.

Parasites of the two relapsing species of Plasmodium, P. ovale and P. vivax, also can

differentiate into a quiescent stage, the hypnozoite, which later can enter into schizogony and

reemerge to invade erythrocytes. P. malariae has the potential to persist at very low levels in

the circulation for decades.

Each species has developed an efficient strategy for erythrocyte invasion that relies on

a specific, complex interaction of certain surface proteins or glycoproteins on the erythrocyte

and a specific ligand of the parasite. For example, P. vivax preferentially invades erythrocytes

bearing the Duffy blood group antigen,1 an antigen that is rarely found on erythrocytes in

persons from West and central Africa. Plasmodium falciparum most efficiently invades

erythrocytes with intact glycosylated forms of the glycophorin family of proteins.2 Parasitic

ligands that facilitate interactions with these erythrocyte molecules have been identified in P.

falciparum and P. vivax. 2,3 P. ovale and P. falciparum invade erythrocytes of all ages while

P. vivax preferentially invade reticulocytes, and P. malariae preferentially invade mature

erythrocytes. Once inside the erythrocyte, parasites can undergo either asexual schizogony or

sexual differentiation to produce gametocytes.

During asexual schizogony, the parasites are known as trophozoites once they are

established inside the erythrocyte; the early trophozoite forms often are called rings because

of their apparent lack of central cytoplasmic staining. Parasites in this stage ferment

homolactate and actively digest the host cell hemoglobin, which they use as a source of

amino acids and energy.4 This activity is accomplished through a set of highly adapted

proteinases in a singularly adapted organelle, the food vacuole.5 The residue of hemoglobin

degradation is an intact tetrapyrrole ring, ferriprotoporphyrin IX, which the parasites detoxify

through polymerization and which can be seen microscopically as malarial pigment.6 This

polymerization step is thought to be the site of action of quinoline-containing antimalarial

compounds, including chloroquine.7,8

The last few hours of the erythrocytic stage of the parasite's lifecycle, when the

parasite is called a schizont, comprise the actual replicative phase in which the parasite

undergoes mitosis and subdivides and differentiates into merozoites. It is the subsequent

rupture and release of merozoites that lead to fever and other malarial symptoms. If infections

are synchronized, the periodicity of symptoms is 48 hours in P. ovale and P. vivax malaria,

whereas it is 72 hours in P. malariae infections. While periodicity may be every 48 hours in

P. falciparum infections, it often is irregular. Indeed, the parasite's reproductive cycles often

are not synchronized with any of the species and the absence of periodicity does not rule

against malaria being the cause of fevers.

Parasites in the erythrocytic stages also can undergo sexual differentiation, a step that

is necessary for transmission. Male and female gametes, which are produced by each

Plasmodium species, remain inside the erythrocyte until they are ingested by the mosquito.

At this point, they undergo further differentiation and join to form a zygote, which

differentiates into an ookinete and invades the mosquito midgut to form the reproductive

oocyst. Sporozoites emerge from the oocyst and migrate to the salivary gland, where they can

reinfect a human during a subsequent blood meal.

In general, all of the erythrocytic asexual and sexual developmental stages of P. ovale,

P. vivax, and P. malariae occur in circulating blood and can be visualized in the peripheral

blood smear. The late trophozoite stages of P. falciparum rarely are seen in the peripheral

circulation because of the development of “knobs” on infected erythrocytes that lead to

adherence of the parasitized erythrocytes to the capillary endothelium.9 Sequestration of

parasites in various organs is believed to be responsible for the clinical manifestations that

occur with P. falciparum infections, such as central nervous system and pulmonary

complications.

No strict immunity develops to malaria, but rather an acquired ability to tolerate

Plasmodium infections occurs, which is a selective process related to the degree of exposure

to a variety of strains.10 Most deaths from malaria occur in children younger than 5 years in

areas of high transmission of P. falciparum. Although P. falciparum can cause lethal

infection in young children or nonimmune individuals, asymptomatic parasitemia is common

in older age groups in highly endemic areas.

Rupture of a large number of erythrocytes at the same time releases a large amount of

pyrogens, causing the paroxysms of malarial fever. The periodicity of malarial fever depends

on the time required for the erythrocytic cycle and is definite for each species. P malariae

needs 72 hours for each cycle, leading to the name quartan malaria. The other 3 species each

take 48 hours for 1 cycle and cause fever on alternate days (tertian malaria). However, this

periodicity requires all the parasites to be developing and releasing simultaneously; if this

synchronization is absent, periodicity is not observed.

Most malaria acquired in Africa is due to P falciparum. P vivax dominates in Asia and

the Americas. The bite of an infected female Anopheles mosquito transmits malaria. Species

of mosquito capable of transmitting malaria are found in all 48 of the contiguous states of the

United States.

Malaria can also be transmitted through blood transfusion. Among people living in

malarious areas, semi-immunity to malaria allows donors to have parasitemia without any

fever or other clinical manifestations. The malaria transmitted is by the merozoites, which do

not enter the liver cells. Because the liver stage is not present, curing the acute attack results

in complete cure. Organ transplantation is another malarial transmission route.

Transplacental malaria (ie, congenital malaria) can be significant in populations who

are semi-immune to malaria. The mother may have placental parasitemia, peripheral

parasitemia, or both, without any fever or other clinical manifestations. Vertical transmission

of this infestation may be as high as 40% and is associated with anemia in the baby.

Figure 2. This micrograph illustrates the trophozoite form, or immature-ring form, of

the malarial parasite within peripheral erythrocytes. Red blood cells infected with

trophozoites do not produce sequestrins and, therefore, are able to pass through the

spleen.

Figure 3. A mature schizont within an erythrocyte. These red blood cells (RBCs) are

sequestered in the spleen when malaria proteins, called sequestrins, on the RBC

surface bind to endothelial cells within that organ. Sequestrins are only on the

surfaces of erythrocytes that contain the schizont form of the parasite.

P. falciparum

The most malignant form of malaria is caused by this species. P falciparum is able to

infect RBCs of all ages, resulting in high levels of parasitemia (>5% RBCs infected). In

contrast, P vivax and P ovale infect only young RBCs and thus cause a lower level of

parasitemia (usually < 2%).

Hemoglobinuria (blackwater fever), a darkening of the urine seen with severe RBC

hemolysis, results from high parasitemia and is often a sign of impending renal failure and

clinical decline.

Sequestration is a specific property of P falciparum. As it develops through its 48-

hour life cycle, the organism demonstrates adherence properties, which result in the

sequestration of the parasite in small postcapillary vessels. For this reason, only early forms

are observed in the peripheral blood before the sequestration develops; this is an important

diagnostic clue that a patient is infected with P falciparum.

Sequestration of parasites may contribute to mental-status changes and coma, observed

exclusively in P falciparum infection. In addition, cytokines and a high burden of parasites

contribute to end-organ disease. End-organ disease may develop rapidly in patients with P

falciparum infection, and it specifically involves the central nervous system (CNS), lungs,

and kidneys.

Other manifestations of P falciparum infection include hypoglycemia, lactic acidosis,

severe anemia, and multiorgan dysfunction due to hypoxia. These severe manifestations may

occur in travelers without immunity or in young children who live in endemic areas.

P. vivax

If this kind of infection goes untreated, it usually lasts for 2-3 months with

diminishing frequency and intensity of paroxysms. Of patients infected with P vivax, 50%

experience a relapse within a few weeks to 5 years after the initial illness. Splenic rupture

may be associated with P vivax infection secondary to splenomegaly resulting from RBC

sequestration. P vivax infects only immature RBCs, leading to limited parasitemia.

P. ovale

These infections are similar to P vivax infections, although they are usually less

severe. P ovale infection often resolves without treatment. Similar to P vivax, P ovale infects

only immature RBCs, and parasitemia is usually less than that seen in P falciparum.

P. malariae

Persons infected with this species of Plasmodium remain asymptomatic for a much

longer period of time than do those infected with P vivax or P ovale. Recrudescence is

common in persons infected with P malariae. It often is associated with a nephrotic

syndrome, possibly resulting from deposition of antibody-antigen complex on the glomeruli.

P. knowlesi

Autochthonous cases have been documented in Malaysian Borneo, Thailand,

Myanmar, Singapore, the Philippines, and other neighboring countries. It is thought that

simian malaria cases probably also occur in Central America and South America. Patients

infected with this, or other simian species, should be treated as aggressively as those infected

with falciparum malaria, as P knowlesi may cause fatal disease.

2.2 Risk factors

Risk factors for malaria include the following:

Residence in, or travel through, a malarious area

No previous exposure to malaria (hence no immunity)

No chemoprophylaxis or improper chemoprophylaxis

2.3 Epidemiology

The epidemiology of malarial infections is intricately linked to the distribution and

habits of the anopheline vectors in any particular region. In highly endemic areas, mosquito

breeding can take place nearly year-round, and reproductive capacity in the mosquito is

maximized by a tropical climate.11 In areas of seasonal transmission its prevalence is

particularly related to rainfall or other ecologic events that affect the mosquito population.

Malaria also can be related to occupation when only certain segments of the population are

exposed to the vectors.

The estimated worldwide incidence of malaria is greater than 350–500 million clinical

malaria episodes per year, with more than 1 million deaths annually, most of which occur in

children younger than 5 years.12 Almost all deaths are due to P. falciparum, with more than

80% occurring in sub-Saharan Africa. Prior to the 1950s, malaria was endemic throughout

the southeastern United States. During the late 1940s, a combination of improved housing

and socioeconomic conditions, water management, vector-control efforts, and case

management was successful at interrupting malaria transmission in the United States. In the

United States today, most cases occur in persons who have traveled to or are emigrating from

malarious areas,13 although transmission also can occur congenitally or through blood

transfusion or organ transplantation. Anopheline vectors are still present in most areas of the

United States, and, occasionally, localized outbreaks of malaria occur because of

transmission from imported human cases.14

Malaria is a major health problem in Africa, Asia, Central America, Oceania, and

South America. About 40% of the world's population lives in areas where malaria is

common.15 Approximately 300-500 million cases of malaria occur every year, and 1-2 million

deaths occur, most of them in young children. People of all races are affected by malaria,

with some exceptions. People of West African origin who do not have the Duffy blood group

are not susceptible to P vivax malaria.

Figure 4. Global spatial distribution of Plasmodium falciparum malaria in 2007 and

preliminary global distribution of Plasmodium vivax malariaThe distribution of P

falciparum malaria was defined by use of reported case data, medical intelligence, and

biological constraints of transmission to identify areas of stable and unstable transmission

and malaria-free areas. The distribution of P vivax malaria shown here is preliminary and

was defined by use of information contained in travel and health guidelines; work by the

Malaria Atlas Project is looking into refining this distribution on the basis of similar

methodologies to those used for the definitions of P falciparum

Children of all ages living in nonmalarious areas are equally susceptible to malaria. In

endemic areas, children younger than age 5 years have repeated and often serious attacks of

malaria. The survivors develop partial immunity. Thus, older children and adults often have

asymptomatic parasitemia (ie, the presence of plasmodia in the bloodstream without the

clinical manifestations of malaria). Most deaths resulting from malaria occur in children

younger than age 5 years.

2. 4. Pathogenesis

The pathophysiology of malaria results from destruction of erythrocytes (both

infected and uninfected), the consequent liberation of parasite and erythrocyte material into

the circulation, and the host reaction to these events. P. falciparum malaria-infected

erythrocytes specifically sequester in the microcirculation of vital organs, interfering with

microcirculatory flow and host tissue metabolism.16

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.

lmmunopathologic events that have been documented in patients with malaria include

polyclonal activation resulting in both hypergammaglobulinemia and the formation of

Immune complexes, immunodepression, and excessive production of proinflammatory

cytokines (tumor necrosis factor) that may produce most of the pathology including tissue

hypoxia.17

Erythrocytes containing mature forms of P. falciparum adhere to microvascular

endothelium (“cytoadherence”) and thus disappear from the circulation. This is called

sequestration, and it starts at ~12 hours of asexual development. The process is accelerated by

fever. Sequestration does not occur to a significant extent with the other human malaria para-

sites. Sequestration is thought to be central to the pathophysiology of falciparum malaria,

since it interferes with microcirculatory flow. Once infected, erthrocytes adhere and do not

enter the circulation again, remaining stuck until they rupture at merogony (schizogony). As a

consequence, whereas in the other malarias of humans, mature parasites are commonly seen

on blood smears, these forms are rare in falciparum malaria and often indicate serious

infection. It was thought that ring-stage infected erythrocytes do not cytoadhere at all, but

recent pathologic and laboratory studies show that they do, although much less so than more

mature stages. Sequestration occurs predominantly in the venules of vital organs. It is greatest

in the brain, particularly in the white matter; prominent in the heart, eyes, liver, kidneys,

intestines, and adipose tissue; and least frequent in the skin. Even within the brain, the

distribution of sequestered erythrocytes varies markedly from vessel to vessel, presumably

reflecting differences in the local expression of endothelial receptors. Cytoadherence and the

related phenomenon of rosetting lead to microcirculatory obstruction in falciparum malaria.

The consequences of microcirculatory obstruction are activation of the vascular endothelium

and reduced oxygen and substrate supply, which leads to anaerobic glycolysis, lactic acidosis,

and cellular dysfunction.16

Immunity after Plasmodium infection is incomplete so that severe disease is averted

but complete eradication or prevention of future infection is not achieved. 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 that

includes 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 owing to passive maternal antibody and high levels of fetal hemoglobin.

Children 3 mo to 2-5 yr 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 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.17

2. 5. Diagnosis

2. 5. 1. Clinical Diagnosis

The sign and symptoms of malaria are nonspecific. Malaria is clinically suspected

mostly on the basis of fever or a history of fever. Diagnosis based on clinical features alone

has very low specificity and results in over-treatment. Other possible causes of fever and the

need for alternative or additional treatment must always be carefully considered. The WHO

recommendations for clinical diagnosis/suspicion of uncomplicated malaria in different

epidemiological settings are as follows : 18

In settings where the risk of malaria is low, clinical diagnosis of uncomplicated

malaria should be based on the possibility of exposure to malaria and a history of

fever in the previous three days with no features of other severe diseases;

In settings where the risk of malaria is high, clinical diagnosis should be based on a

history of fever in the previous 24 h and/or the presence of anemia, for which pallor

of the palms appears to be the most reliable sign in young children.

In all settings, clinical suspicion of malaria should be confirmed with a parasitological

diagnosis. However, in settings where parasitological diagnosis is not possible, the decision

to provide antimalarial treatment must be based on the prior probability of the illness being

malaria. Other possible causes of fever and need for alternative treatment must always be

carefully considered.

Fever, headache, and malaise are commonly the first manifestations. An important

consideration is that up to half of patients may not be febrile when they present to physician,

although 78% to 100% of patients will have a history of fever. 2 The classic symptoms of

cyclic fevers, rigors, and cold sweats are often not present. Historically, fever cycles were

used to diagnose and differentiate malarial species, but the sensitivity and specificity of this

method are poor. Diarrhea, vomiting, back pain, myalgias, sore throat, or cough may

predominate, frequently distracting clinicians from diagnosis. With the exceptions of fever,

there are no signs that consistently help with the diagnosis in mild, uncomplicated disease.

Splenomegaly is seen in 24% to 40% of cases of uncomplicated malaria and is probably more

common as disease severity increases. With disease progression, clinical sign of

thrombocytopenia, anemia, and jaundice may become apparent, although these are not

universal. However, given the lack of sensitivity and specificity of these tests, all suspected

cases need definitive laboratory diagnosis, usually using microscopy of blood.19

Untreated falciparum malaria in a non-immune individual can progress within hours

to life-threatening illness, and, in rural settings, most malaria deaths occur outside hospital.20

Approximately 10% of imported malaria will progress to complicated or severe malaria.19

Table 1. Case definition of severe malaria 19

2. 5. 2. Parasitological Diagnosis

The changing epidemiology of malaria and the introduction of ACTs have increased

the urgency of improving the specificity of malaria diagnosis. Parasitological diagnosis has

the following advantages.18

Improved patient care in parasite-positive patients

Identification of parasite-negative patients in whom another diagnosis must be sought

Prevention of unnecessary use of antimalarials, reducing frequency of adverse effects,

especially in those who do not need the medicines, and drug pressure selecting for

resistant parasites

Improved malaria case detection and reporting

Confirmation of treatment failures

The two methods in routine use for parasitological diagnosis are light microscopy and rapid

diagnostic test (RDTs). The latter detect parasite-specific antigens or enzymes and some have

a certain ability to differentiate species. Deployment of microscopy and RDTs must be

accompanied by quality assurance. Antimalarial treatment should be limited to test positive

case and negative cases should be reassessed for other common causes of fever. 18

Light Microscopy

Light microscopy has long been considered the ‘gold standard’ for malaria diagnosis.

When performed under optimal conditions, light microscopy can detect parasitemia as low as

5 parasites/µL or 0.0001% on thick blood smears. Microscopy also allows the identification

of the species of malaria and quantification of the density of parasite infection, especially on

thin smears. Speciation is important clinically because it guides treatment choice, particularly

when P.vivax or P.ovale are identified. These species may have dormant liver hypnozoites

that cannot be detected with current diagnostic tools and require eradication with primaquine

therapy. Because microscopy can provide a quantitative evaluation of parasitemia, it is the

preferred method for monitoring response to treatment in patients with severe malaria. It also

permits differentiation between asexual parasite stages, which are clinically significant, and

gametocytes, which contribute to ongoing transmission of the parasite but which do not

contribute to illness. 21 In a patient suspected of having malaria with a negative blood smears,

the blood smears should be examined every 12 hours for 36-48 hours before considering it to

be negative.16

The quality of malaria microscopy is dependent on the quality of the reagents used to

stain the blood smear, the microscope, the experience of the microscopist reading the smear,

the time spent reading the smear, and the skill with which the blood smear was prepared on

the slide. There are different staining techniques available for malaria microscopy.

Traditionally, Giemsa stain is the preferred staining method for routine use in the field and in

studies with reference microscopy. Field’s stain (water-based Romanovsky stain) may also

produce reliable results but fades rapidly and is, therefore, unsuitable for slides that require

later review. 16

Thin Blood Films

Preparation of the smear and staining are similar to those used for normal hematology,

except that ordinary Giemsa’s stain is used, and dilution is made in buffered distilled water

(pH 7.2) instead of the usual slightly acidic buffer (pH 6.8) used by hematologists. The

buffered water at pH 7.2 must be used. It is only at this alkaline pH that proper differentiation

of parasite nuclear and cytoplasmic material takes place, as well as the staining of

cytoplasmic and membrane changes in infected RBCs (e.g. Maurer’s clefts in falciparum and

Schuffners and James’ dots in vivax and ovale, respectively). Both sensitivity and specificity

are defective in the use of acidic staining. 22

Method (Giemsa’s stain) : 22

1. Allow the film to dry in air and fix with methanol for ½ to 1 minute

2. Tip off excess methanol and place face down on a staining tray

3. Using the 20 ml syringe and blunt needle, dilute the stock Giemsa 1:10 with buffered

distilled water. Mix well and expel air

4. Infiltrate the stain, using the syringe and needle, under the slide, taking care not to

trap large air bubbles. Stain for 40-45 minutes

5. At the end of the staining time, rise the slide briefly with tap water and allow them to

drain dry in a vertical position.

Thick Blood Films

Thick blood films allow a rapid examination of relatively large volume of blood,

enabling the detection of scanty parasitemias. In unit time, a well prepared thick blood film

gives a ten fold increase in sensitivity over thin films, although 40 times the volume of blood

is examined. Two staining techniques are usually employed: Field’s technique, which

demands expertise for the best results, and the slower Giemsa’s method, which gives a more

predictable but less attractive result. 22

Interpretation of Stained Thin Films

The presence of intraerythrocytic bodies, generally consisting of a blue staining

cytoplasmic area closely associated with a small reddish-staining nuclear area, and, in the

larger, more mature parasites, the presence within the organism of yellow-brown to black

malaria pigment, are diagnostic of malaria infection. As the malaria parasite grows within the

erythrocyte, and finally divides to a maximum of 24 infective merozoites, the host cell may

show enlargement (P.vivax and P.ovale), remain the same size or shrink (P.falciparum and

P.malariae). the erythrocyte membrane may develop surface markings which stain pink with

Giemsa (P.vivax and P.ovale). All stages of the parasite may be seen in the peripheral blood

in the case of P.vivax, ovale, and malariae, but generally only the ring parasites and (in older

infections) the banana-like gametocytes) are found in P.falciparum. In infections of

P.falciparum, a few irregularly spaced intraeryhtrocytic inclusions of different sizes appear,

particularly noticeable in erythrocytes with more mature forms. These are termed Maurer’s

clefts, and should be distinguished carefully from the finer, much more numerous Schuffner’s

dots found on the RBC membrane in P.vivax and ovale. The dots in P.ovale are sometimes

referred to as James’ dots. 22

Figure 5. Diagnostic forms of Malaria 16

Figure 6. P.falciparum staging 16

Figure 7. P.vivax staging16

Estimation of Parasite Density

Since one criterion for diagnosing severe malaria is the density of parasitemia, it is

important, particularly in P. falciparum infections, to determine the parasite density. This is

expressed as the percentage of erythrocytes parasitized, or as the numbers of parasitized

erythrocytes/μL blood. Percent parasitemia is estimated by determining the number of

parasitized erythrocytes/1000 red cells in a thin blood film. At low densities of parasitemia

percent parasitemia is extremely difficult to determine, and the number of parasites/μL blood

is estimated. The number of parasites/μL blood is derived from the number of parasitized

erythrocytes/200 white blood cells (WBCs), generally in a thick blood film. If the WBC

count is known, then one can calculate the parasite density per microliter. For example, if

there are 100 parasites/200 WBCs and the WBC count is 6000/μL, the parasite density is

(100 parasites/200 WBCs) × 6000 WBCs/μL = 3000 parasites/μL blood. If the WBC count is

not known, it is generally assumed to be 8000 WBCs/μL. The number of parasites/μL blood

can also be estimated by knowing the percent parasitemia and the number of erythrocytes/μL

blood. If there are 5 × 106 erythroctyes/μL blood, then a 1% parasitemia corresponds to 50

000 parasitized erythrocytes/μL blood. An expert microscopist who examines 200 fields of a

thick blood film at 1000× magnification can detect approximately 5 parasitized

erythroctyes/μL blood, which for an individual with 5 × 106 erythroctyes/μL blood is a

percent parasitemia of 0.0001%. In routine practice densities less than 50/μL are usually

reported as negative.16

2. 5. 3. Rapid Diagnostic Tests

Rapid, simple, sensitive, and specific antibody-based diagnostic stick or card tests

(RDTs) detect P. falciparum-specific, histidine-rich protein (HRP) or lactate dehydrogenase

antigens. Some of these tests incorporate a second antibody, which allows falciparum

malaria to be distinguished from the less dangerous malarias. P. falciparum HRP2-based tests

may remain positive for several weeks after acute infection. This is a disadvantage in high-

transmission areas where infections are highly prevalent but is of value in the diagnosis of

severe malaria in patients who have taken antimalarial drugs and cleared peripheral

parasitemia. The World Health Organization (WHO) has assessed the performance of

available RDTs. There is wide variation in the performance of current commercially available

tests. Although an expert microscopist can detect as few as 5 parasites/μL blood, in general,

microscopy and RDTs have similar levels of detection at ~50 parasites/μL. A parasitemia of

50/μL corresponds to a total body parasite burden in an adult of >100 million parasites and a

percent parasitemia of 0.001%.16

The choice between RDTs and microscopy depends on local circumstances, including

the skills available, patient case-load, epidemiology of malaria and the possible use of

microscopy for the diagnosis of other diseases. Where the case-load of fever patient is high,

microscopy is likely to be less expensive than RDTs, but may be less operationally feasible.

Microscopy has further advantages in that it can be used for speciation and quantification of

parasites, and to assess response to antimalarial treatment. Microscopy can also be used in the

identification of other causes of fever. However, a major drawback of light microscopy is its

requirement for well-trained, skilled staff, and energy source to power the microscope.

The sensitivities and specificities of RDTs are variable, and their vulnerability to high

temperatures and humidity is an important constraint. Despite these concerns, RDTs make it

possible to expand the use of confirmatory diagnosis.

In the diagnosis of severe malaria cases, microscopy is a preferred option, it not only

provides the diagnosis of malaria, but it is useful in assessing other important parameters in a

severely ill patient. In situations where an RDT has been used to confirm malaria, this allows

for a rapid institution of antimalarial treatment, however, where possible a microscopic

examination is recommended to enhance the overall management of the patient.18

2. 6. Treatment

It is preferable that treatment for malaria should not be initiated until the diagnosis has

been established by laboratory investigations. “Presumptive treatment” without the benefit of

laboratory confirmation should be reserved for extreme circumstances (strong clinical

suspicion, severe disease, impossibility of obtaining prompt laboratory diagnosis). 23

Once the diagnosis of malaria has been made, appropriate antimalarial treatment must

be initiated immediately. Treatment should be guided by three main factors: 23

The infecting Plasmodium species

The clinical status of the patient

The drug susceptibility of the infecting parasites as determined by the geographic area

where the infection was acquired and the previous use of antimalarial medicines.

The infecting Plasmodium species: Determination of the infecting Plasmodium

species for treatment purposes is important for three main reasons. Firstly, P. falciparum and

P. knowlesi infections can cause rapidly progressive severe illness or death while the other

species, P. vivax, P. ovale, or P. malariae, are less likely to cause severe manifestations.

Secondly, P. vivax and P. ovale infections also require treatment for the hypnozoite forms

that remain dormant in the liver and can cause a relapsing infection. Finally, P. falciparum

and P. vivax species have different drug resistance patterns in differing geographic regions.

For P.falciparum and P.knowlesi infections, the urgent initiation of appropriate therapy is

especially critical.

The clinical status of the patient: Patients diagnosed with malaria are generally

categorized as having either uncomplicated or severe malaria. Patients diagnosed with

uncomplicated malaria can be effectively treated with oral antimalarials. However, patients

who have one or more of the following clinical criteria (impaired consciousness/coma, severe

normocytic anemia [hemoglobin<7], renal failure, acute respiratory distress syndrome,

hypotension, disseminated intravascular coagulation, spontaneous bleeding, acidosis,

hemoglobinuria, jaundice, repeated generalized convulsions, and/or parasitemia of > 5%) are

considered to have manifestations of more severe disease and should be treated aggressively

with parenteral antimalarial therapy.

The drug susceptibility of the infecting parasites: Finally, knowledge of the

geographic area where the infection was acquired provides information on the likelihood of

drug resistance of the infecting parasite and enables the treating clinician to choose an

appropriate drug or drug combination and treatment course. In addition, if a malaria infection

occurred despite use of a medicine for chemoprophylaxis, that medicine should not be a part

of the treatment regimen. If the diagnosis of malaria is suspected and cannot be confirmed, or

if the diagnosis of malaria is confirmed but species determination is not possible, antimalarial

treatment effective against chloroquine-resistant P. falciparum must be initiated immediately.

Treatment for Infants and Young Children

There are important differences in the pharmacokinetic parameters of many medicines

in young children. Accurate dosing is particularly important in infants. Despite this, only a

few clinical studies have focused specifically on this age range; this is partly because of

ethical considerations relating to the recruitment of very young children to clinical trials, and

it is also because of the difficulty of repeated blood sampling. The artemisinin derivatives are

safe and well tolerated by young children, and so the choice of ACT will be determined

largely by the safety and tolerability of the partner drug. Sulfadoxine-pyrimethamine should

be avoided in the first weeks of life because it competitively displaces bilirubin with the

potential to aggravate neonatal hyperbilibinemia. Primaquine should also be avoided in the

first month and tetracyclines avoided throughout infancy and in children < 8 years of age.

With these exceptions there is no evidence for specific serious toxicity for any of the other

currently recommended antimalarial treatments in infancy.

Treatment of Uncomplicated P.falciparum Malaria

To counter the threat of resistance of P. falciparum to monotherapies, and to improve

treatment outcome, WHO recommends that artemisinin-based combination therapies be used

for the treatment of uncomplicated P. falciparum malaria. Although the evidence base

confirming the benefits of artemisinin-based combinations has grown substantially in recent

years, there is still substantial geographic variability in the efficacy of available ACT options,

underlining the importance of countries regularly monitoring the efficacy of the ACTs in use

to ensure that the appropriate ACT option(s) is being deployed.

Uncomplicated malaria is defined as symptomatic malaria without signs of severity or

evidence (clinical or laboratory) of vital organ dysfunction. The signs and symptoms of

uncomplicated malaria are nonspecific. Malaria is, therefore, suspected clinically mostly on

the basis of fever or a history of fever. 18

Non-artemisinin based combination therapy

Non-artemisinin based combination treatments include sulfadoxine-pyrimethamine

plus chloroquine (SP+CQ) or amodiaquine (SP+AQ). The prevailing high levels of resistance

to these medicines as monotherapy have compromised their efficacy even in combinations.

There is no convincing evidence that chloroquine plus sulfadoxinepyrimethamine provides

any additional benefit over SP, so this combination is not recommended; amodiaquine plus

sulfadoxine-pyrimethamine can be more effective than either drug alone; but it is usually

inferior to ACTs, and it is no longer recommended for the treatment of malaria.18

Artemisinin-based combination therapy

These are combinations in which one of the components is artemisinin and its

derivatives (artesunate, artemether, dihydroartemisinin). The artemisinins produce rapid

clearance of parasitaemia and rapid resolution of symptoms, by reducing parasite numbers

100- to 1000-fold per asexual cycle of the parasite (a factor of approximately 10 000 in each

48-h asexual cycle), which is more than the other currently available antimalarials achieve.

Because artemisinin and its derivatives are eliminated rapidly, when given alone or in

combination with rapidly eliminated compounds (tetracyclines, clindamycin), a 7-day course

of treatment with an artemisinin compound is required. This long duration of treatment with

the artemisinins can be reduced to 3 days when given in combination with slowly eliminated

antimalarials. With this shorter 3-day course, the complete clearance of all parasites is

dependent on the partner medicine being effective and persisting at parasiticidal

concentrations until all the infecting parasites have been killed. Thus, the partner compounds

need to be relatively slowly eliminated. This also results in the artemisinin component being

protected from resistance by the partner medicine, while the partner medicine is also partly

protected by the artemisinin derivative. An additional advantage from a public health

perspective is the ability of the artemisinins to reduce gametocyte carriage and, thus, the

transmissibility of malaria. This contributes to malaria control, particularly in areas of low-to-

moderate endemicity. To eliminate at least 90% of the parasitaemia, a 3-day course of the

artemisinin is required to cover up to three post-treatment asexual cycles of the parasite. This

ensures that only about 10% of the parasitamia is present for clearance by the partner

medicine, thus reducing the potential for development of resistance. Shorter courses of 1–2

days of the artemisinin component of the ACTs would lead to a larger proportion of

parasitaemia for clearance by the partner medicine. 18

In summary, the ACT options now recommended for treatment of uncomplicated

falciparum malaria in alphabetical order are:

artemether plus lumefantrine,

artesunate plus amodiaquine,

artesunate plus mefloquine,

artesunate plus sulfadoxine-pyrimethamine,

dihydroartemisinin plus piperaquine

Table 2. Treatment for Uncomplicated P. falciparum Malaria

Artemether plus lumefantrine

This is currently available as a fixed-dose formulation with dispersible or standard tablets

containing 20 mg of artemether and 120 mg of lumefantrine.

Therapeutic dose. The recommended treatment is a 6-dose regimen over a 3-day period. The

dosing is based on the number of tablets per dose according to pre-defined weight bands (5–

14 kg: 1 tablet; 15–24 kg: 2 tablets; 25–34 kg: 3 tablets; and > 34 kg: 4 tablets), given twice a

day for 3 days. This extrapolates to 1.7/12 mg/kg body weight of artemether and

lumefantrine, respectively, per dose, given twice a day for 3 days, with a therapeutic dose

range of 1.4–4 mg/kg of artemether and 10–16 mg/kg of lumefantrine.

Artesunate plus amodiaquine

This is currently available as a fixed-dose formulation with tablets containing 25/67.5 mg,

50/135 mg or 100/270 mg of artesunate and amodiaquine. Blister packs of separate scored

tablets containing 50 mg of artesunate and 153 mg base of amodiaquine, respectively, are

also available.

Therapeutic dose. A target dose of 4 mg/kg/day artesunate and 10 mg/kg/day amodiaquine

once a day for 3 days, with a therapeutic dose range between 2–10 mg/kg/day artesunate and

7.5–15 mg/kg/dose amodiaquine.

Artesunate plus mefloquine

This is currently available as blister packs with separate scored tablets containing 50 mg of

artesunate and 250 mg base of mefloquine, respectively. A fixed-dose formulation of

artesunate and mefloquine is at an advanced stage of development.

Therapeutic dose. A target dose of 4 mg/kg/day artesunate given once a day for 3 days and

25 mg/kg of mefloquine either split over 2 days as 15mg/kg and 10mg/kg or over 3 days as

8.3 mg/kg/day once a day for 3 days. The therapeutic dose range is between 2– 10

mg/kg/dose/day of artesunate and 7–11 mg/kg/dose/day of mefloquine.

Artesunate plus sulfadoxine-pyrimethamine

This is currently available as separate scored tablets containing 50 mg of artesunate and

tablets containing 500 mg of sulfadoxine and 25 mg of pyrimethamine.

Therapeutic dose. A target dose of 4 mg/kg/day artesunate given once a day for 3 days and a

single administration of 25/1.25 mg/kg sulfadoxine-pyrimethamine on day 1, with a

therapeutic dose range between 2–10 mg/kg/day artesunate and 25–70/1.25–3.5 mg/kg

sulfadoxine pyrimethamine.

Dihydroartemisinin plus piperaquine

This is currently available as a fixed-dose combination with tablets containing 40 mg of

dihydroartemisinin and 320 mg of piperaquine.

Therapeutic dose. A target dose of 4 mg/kg/day dihydroartemisinin and 18 mg/kg/day

piperaquine once a day for 3 days, with a therapeutic dose range between 2–10 mg/kg/day

dihydroartemisinin and 16–26 mg/kg/dose piperaquine.

Treatment of Severe P.falciparum Malaria

Death from severe malaria often occurs within hours of admission to hospital or

clinic, so it is essential that therapeutic concentrations of antimalarial drug be achieved as

soon as safely possible. This is why a loading dose of certain drugs is essential, particularly

quinine, quinidine, and artemether. Nearly all cases of severe malaria result from P.

falciparum infection. Many patients with malaria, including those with species other than P.

falciparum, cannot take oral medications initially because of repeated vomiting. They do not

fulfill the criteria of severe malaria but do require parenteral (or rectal) administration of

antimalarials. In practice if there is uncertainty the patient should be treated as having severe

malaria until able to swallow medications reliably. Delays in reaching a hospital or health

center may be fatal for patients who cannot swallow oral medications reliably. The pre-

referral administration of a rectal formulation of artesunate has been shown in a large trial to

reduce the mortality from malaria in children under 5 years by 25%.16

Following initial parenteral treatment, once the patient can tolerate oral therapy, it is

essential to continue and complete treatment with an effective oral antimalarial using a full

course of an effective ACT (artesunate plus amodiaquine or artemether plus lumefantrine or

dihydroartemisinin plus piperaquine) or artesunate (plus clindamycin or doxycycline) or

quinine (plus clindamycin or doxycycline). Doxycycline is preferred to other tetracyclines

because it can be given once daily, and does not accumulate in renal failure. But as treatment

with doxycycline only starts when the patient has recovered sufficiently, the 7-day

doxycycline course finishes after the quinine, artemether or artesunate course. Where

available, clindamycin may be substituted in children and pregnant women; doxycycline

cannot be given to these groups. Regimens containing mefloquine should be avoided, if the

patient presented initially with impaired consciousness. This is because of an increased

incidence of neuropsychiatric complications associated with mefloquine following cerebral

malaria.18

Table 3. Treatment of Severe Malaria16

Treatment of Uncomplicated P.vivax Malaria

P. vivax, the second most important species causing human malaria, accounts for

about 40% of malaria cases worldwide; it is the dominant malaria species outside Africa. It is

prevalent in endemic areas in the Asia, Central and South America, Middle East and Oceania.

In Africa, it is rare, except in the Horn, and it is almost absent in West Africa. In most areas

where P. vivax is prevalent, malaria transmission rates are low, and the affected populations,

therefore, achieve little immunity to this parasite. Consequently, people of all ages are at risk.

The other two human malaria parasite species P. malariae the tropical areas of Africa. Further

information on treatment is provided in Annex 9. Among the four species of Plasmodium that

affect humans, only P. vivax and P. ovale form hypnozoites, parasite stages in the liver,

which can result in multiple relapses of infection weeks to months after the primary infection.

Thus, a single infection causes repeated bouts of illness. The objective of treating malaria

caused by P. vivax and P. ovale is to cure (radical cure) both the blood stage and the liver

stage infections, and, thereby, prevent both recrudescence and relapse, respectively. Infection

with P. vivax during pregnancy, as with P. falciparum, reduces birth weight. In

primigravidae, the reduction is approximately two thirds of that associated with P. falciparum

(110 g compared with 170 g), but this adverse effect does not decline with successive

pregnancies, unlike with P. falciparum infections.18

Blood Stage Infection

For chloroquine-sensitive vivax malaria (i.e. in most places where P. vivax is

prevalent), oral chloroquine at a total dose of 25 mg base/kg body weight is effective and

well tolerated. Lower total doses are not recommended, as these might encourage the

emergence of resistance. Chloroquine is given in an initial dose of 10 mg base/kg body

weight followed by either 5 mg/kg body weight at 6 h, 24 h and 48 h or, more commonly, by

10 mg/kg body weight on the second day and 5 mg/kg body weight on the third day. Recent

studies have also demonstrated the efficacy of the recommended ACTs in the treatment of

vivax malaria. The exception to this is artesunate plus sulfadoxine-pyrimethamine. Though

there has been one study from Afghanistan reporting good efficacy to AS+SP, it appears that

P. vivax has developed resistance to sulfadoxine-pyrimethamine more rapidly than P.

falciparum has; hence, artesunate plus sulfadoxine-pyrimethamine may not be effective

overall against P. vivax in many areas.16,18

Liver stage infection

To achieve a radical cure, relapses must be prevented by giving primaquine. The

frequency and pattern of relapses varies geographically. Whereas 50–60% of P. vivax

infections in South-East Asia relapse, the frequency is lower in Indonesia (30%) and the

Indian subcontinent (15–20%). Some P. vivax infections in the Korean peninsula (now the

most northerly of human malarias) have an incubation period of nearly one year. Moreover,

the P. vivax populations emerging from hypnozoites commonly differ from the populations

that caused the acute episode. Activation of heterologous hypnozoites populations is the most

common cause of the first relapse in patients with vivax malaria. Thus, the preventive

efficacy of primaquine must be set against the prevalent relapse frequency. It appears that the

total dose of 8-aminoquinoline given is the main determinant of curative efficacy against

liver-stage infection. In comparison with no primaquine treatment, the risk of relapse

decreased by the additional milligram per kilogram body weight of

primaquine given. Primaquine should be given for 14 days.16,18

Table 4. Treatment of Uncomplicated Vivax Malaria 18

Treatment of malaria caused by P.ovale and P. malariae

Resistance of P. ovale and P. malariae to antimalarials is not well characterized and

infections caused by these two species are considered to be generally sensitive to

chloroquine. Only one study, conducted in Indonesia, has reported resistance to chloroquine

in P. malariae. The recommended treatment for the relapsing malaria caused by P. ovale is

the same as that given to achieve radical cure in vivax malaria, i.e. with chloroquine and

primaquine. P. malariae should be treated with the standard regimen of chloroquine as for

vivax malaria, but it does not require radical cure with primaquine, as no hypnozoites are

formed in infection with this species.18,20

2. 7 Differential Diagnosis

The differential diagnosis of malaria is broad and includes viral infections such as

influenza and hepatitis, sepsis, pneumonia, meningitis, encephalitis, endocarditis,

gastroenteritis, pyelonephritis, babesiosis, brucellosis, leptospirosis, tuberculosis, relapsing

fever, typhoid fever, yellow fever, amebic liver abscess, Hodgkin disease, and collagen

vascular disease.17

2. 8. Complication

Patients with severe malaria should be treated in an ICU. Should clinical deterioration to severe malaria occur, it usually develops 3–7 days after fever onset, although there have been rare reports of nonimmune patients dying within 24 hours of developing symptoms. Severe malaria may develop even after initial treatment response and complete clearance of parasitemia due to delayed cytokine release.

1. Neurologic complications

Cerebral malaria is the most common clinical presentation and cause of death in adults with severe malaria. The onset may be dramatic with a generalized convulsion, or gradual with initial drowsiness and confusion, followed by coma lasting from several hours to several days. The strict definition of cerebral malaria requires the presence of P. falciparum parasitemia and the patient to be unrousable with a Glasgow Coma Scale score of 9 or less, and other causes (e.g. hypoglycemia, bacterial meningitis and viral encephalitis) ruled out.24

From a practical standpoint, any alteration in mental status should be treated as cerebral malaria. A lumbar puncture should be performed to rule out bacterial meningitis. To distinguish cerebral malaria from transient postictal coma, unconsciousness should persist for at least 30 min after a convulsion. The deeper the coma, the worse is the prognosis. On examination, neurologic abnormalities resemble those of a diffuse symmetric encephalopathy, similar to a metabolic encephalopathy. Nuchal rigidity and focal neurologic signs are rare. Corneal and pupillary reflexes are usually intact. The plantar responses are extensor in about half of the patients. Convulsions are usually generalized, with nonspecific abnormalities on electroencephalographic examination. Computed tomography or magnetic resonance imaging often shows evidence of mild cerebral swelling; marked edema or focal lesions are unusual. Delirium, agitation, and even transient paranoid psychosis may develop as the patient recovers consciousness. Apart from cerebral malaria, other neurologic sequelae can occur, such as cranial nerve abnormalities, extrapyramidal tremor, and ataxia.

Several hypotheses have been proposed to explain the pathophysiology of cerebral malaria, but none have been completely satisfactory. The excellent neurologic recovery argues against ischemia alone being the culprit. Raised intracranial pressure, at least in nonimmune adults, appears not to play an important role in the pathogenesis of cerebral malaria. The mortality of cerebral malaria ranges from 10% to 50% with treatment. Most survivors (>97% adults and >90% children) have no neurologic abnormalities on hospital discharge 25.

2. Pulmonary complicationsAcute lung injury usually occurs a few days into the disease course. It may develop

rapidly, even after initial response to antimalarial treatment and clearance of parasitemia. The first indications of impending pulmonary edema include tachypnea and dyspnea, followed by hypoxemia and respiratory failure requiring intubation. Pulmonary edema is usually noncardiogenic and may progress to acute respiratory distress syndrome (ARDS) with an increased pulmonary capillary permeability.26 Acute lung injury is defined as the acute onset of bilateral pulmonary infiltrates with an arterial oxygen tension/fractional inspired oxygen

ratio of 300 mmHg or less, a pulmonary artery wedge pressure of 18 mmHg or less, and no evidence of left atrial hypertension. ARDS is defined as acute lung injury and an arterial oxygen tension/fractional inspired oxygen ratio of 200 mmHg or less.27 Volume overload and hypoalbuminemia may aggravate pulmonary capillary leakage. Chest radiograph abnormalities range from confluent nodules to basilar and/or diffuse bilateral pulmonary infiltrates. Noncardiogenic pulmonary edema rarely occurs with P. vivax and P. ovale malaria.

3. Renal complicationsAcute renal failure is usually oliguric (<400 ml/day) or anuric (<50 ml/day), rarely

nonoliguric, and may require temporary dialysis.28 Urine sediment is usually unremarkable. In severe cases, acute tubular necrosis may develop secondary to renal ischemia.29 The term 'blackwater fever' refers to passage of dark red, brown, or black urine secondary to massive intravascular hemolysis and resulting hemoglobinuria. Usually, this condition is transient and not accompanied by renal failure.

4. HypoglycemiaHypoglycemia is a common feature in patients with severe malaria. It may be

overlooked because all clinical features of hypoglycemia (anxiety, dyspnea, tachycardia, sweating, coma, abnormal posturing, generalized convulsions) are also typical of severe malaria itself. Hypoglycemia may be caused by quinine- or quinidine-induced hyperinsulinemia, but it may be found also in patients with normal insulin levels.

5. Hypotension and shockMost patients with shock exhibit a low peripheral vascular resistance and elevated

cardiac output. Cardiac pump function appears remarkably well preserved despite intense sequestration of parasitized erythrocytes in the microvasculature of the myocardium. Postural hypotension may be secondary to autonomic dysfunction. Severe hypotension can develop suddenly, usually with pulmonary edema, metabolic acidosis, sepsis, and/or massive hemorrhage due to splenic rupture or from the gastrointestinal tract.

6. Hematologic abnormalitiesSevere anemia is more common in children in highly endemic areas due to repeated or chronic Plasmodium infections. Thrombocytopenia is common, but usually not associated with bleeding. Disseminated intravascular coagulation is reported in fewer than 10% of patients with severe malaria.

2. 9. Prognosis Uncomplicated malaria due to P vivax,P malariae, and P ovale has an excellent

prognosis. Most patients have a full recovery with no sequelae. Malaria due to P falciparum is dangerous; if it is not treated quickly and completely, complicated and severe malaria can result, which carries a grave prognosis. Malaria in children younger than age 5 years carries the worst prognosis in endemic areas. In a nonimmune population, malaria is equally deadly at all ages. Repeated attacks of malaria can lead to chronic anemia, malnutrition, and stunted growth. Acidosis, seizures, impaired consciousness, renal impairment, and pre-existing chronic diseases are associated with poor outcomes in children with severe malaria. Other markers of poor outcomes are hyperparasitemia, respiratory distress, young age, severe anemia, and hypoglycemia.30

Internationally, malaria is responsible for approximately 1-3 million deaths per year. Of these deaths, the overwhelming majority are in children aged 5 years or younger, and 80-90% of the deaths each year are in rural sub-Saharan Africa.31 Malaria is the world’s fourth leading cause of death in children younger than age 5 years. Malaria is preventable and treatable. However, the lack of prevention and treatment due to poverty, war, and other economic and social instabilities in endemic areas results in millions of deaths each year.

CHAPTER 4

DISCUSSION AND SUMMARY

4.1 Disscussion

AR, male, 9 years old was admitted to Pediatrics Department of Haji Adam Malik

General Hospital and was diagnosed with malaria. The diagnosis was established based on

history taking, clinical manifestations, physical examination and laboratory finding. From

history taking and clinical manifestations patient experienced periodic fever, fever

intermittently increased and decreased, fever was accompanied with shivering, sweating a

lot was experienced after one fever period, vomiting, pallor, diminished apetite. AR lived

in Padang Sidempuan which is endemic area of malaria, it means patient has partial

immunity.

Risk factors for malaria include the following; Residence in, or travel through, a

malarious area, no previous exposure to malaria (hence no immunity), no

chemoprophylaxis or improper chemoprophylaxis. The clinical features of malaria are

dependent on the malaria-specific immune status of the host and the infecting species of

Plasmodium. Nonimmune people, such as those who have not resided in an endemic area

or have been away from an endemic area for as little as 1 year, generally have symptomatic

infection. Fever can be very high from the first day. Temperatures of 40°C and higher are

often observed. Fever is usually continuous or irregular. Classic periodicity may be

established after some days. High fever, poor oral intake, and vomiting all contribute to

dehydration.

From physical examination in this patient was found pale inferior conjunctiva

palpebra at both eyes. Liver and spleen were not palpable. Laboratory result for this patient

was anemia normokromik-normositik and trombositopenia. From blood smear in the

patient was found P. vivax. Of patients infected with P vivax, 50% experience a relapse

within a few weeks to 5 years after the initial illness.

The liver may be slightly tender. Splenomegaly takes many days, especially in the

first attack in nonimmune children. In children from an endemic area, severe splenomegaly

sometimes occurs. Prolonged malaria can cause anemia. Also, with heavy parasitemia and

large-scale destruction of erythrocytes, mild jaundice may occur. This jaundice subsides

with the treatment of malaria.Splenic rupture may be associated with P vivax infection

secondary to splenomegaly resulting from RBC sequestration. P vivax infects only

immature RBCs, leading to limited parasitemia. The degree of parasitemia hadn’t reached

until 5 % which mean that this patient is categorized for moderate malaria.

Light microscopy has long been considered the ‘gold standard’ for malaria diagnosis.

When performed under optimal conditions, light microscopy can detect parasitemia as low

as 5 parasites/µL or 0.0001% on thick blood smears. Microscopy also allows the

identification of the species of malaria and quantification of the density of parasite

infection, especially on thin smears. Speciation is important clinically because it guides

treatment choice, particularly when P.vivax or P.ovale are identified. Thick blood films

allow a rapid examination of relatively large volume of blood, enabling the detection of

scanty parasitemias. In this patient, P.vivax was found by light microscopy with parasite

density: Trophozoit 7560/µL blood and gametocyte 3880/µL blood.

Normochromic, normocytic anemia is usual in acute malaria. The leukocyte count is

generally normal, although it may be raised in very severe infections, and lowered in early

mild infections. The erythrocyte sedimentation rate, plasma viscosity, and levels of C-

reactive protein and other acute-phase proteins are high. The platelet count is usually

reduced to approximately 105/μL. Severe infections may be accompanied by prolonged

prothrombin and partial thromboplastin times and by more severe thrombocytopenia. In

uncomplicated malaria, plasma concentrations of electrolytes, blood urea nitrogen, and

creatinine are usually normal, or minimally altered. Findings in severe malaria may include

metabolic acidosis, with low plasma concentrations of glucose, sodium, bicarbonate,

calcium, phosphate, and albumin together with elevations in lactate, blood urea nitrogen,

creatinine, urate, muscle and liver enzymes, and conjugated and unconjugated bilirubin.

The patient is admitted to the hospital on 1st October with hemoglobin 8,5 gr % and

the status for iron is normal based on finding of serum iron, TIBC and serum ferritin. On 8 th

October patient’s hemoglobin is 7,8 gr% and we gave the patient packed red cell

transfusion. On the 11th October patient’s hemoglobin was increased until 13,9 gr%. The

laboratory result for G6PD is negative that allows administration of primaquine. The

treatment given were IVFD D5% NaCl 0.45% 15 gtt/i (micro), Paracetamol tab 3 x 300 mg

(k/p), Dalprex 1 x 2 tab for 6 days, Primaquine 1 x ½ tab for 14 days, Transfussion PRC

425 ml.

WHO had recommended administration of ACTs (Artemisin-based Combination

Therapy) to counter the threat of resistance to monotherapies, and to improve treatment

outcome. This patient was administered Dalprex containing 40 mg of dihydroartemisinin

and 320 mg of piperaquine.

If the infecting species is identified as P. vivax or P. ovale, treatment with primaquine

is also necessary to prevent relapse from latent hypnozoite forms in the liver. Glucose-6-

phosphate dehydrogenase (G6PD) deficiency must be ruled out prior to giving primaquine.

Primaquine therapy should be initiated concomitantly with the blood schizonticide as there

is evidence that this results in greater efficacy in eradicating hypnozoites. Primaquine

treatment of a confirmed P. vivax or P. ovale infection in a known G6PD-deficient

individual should only be used after a careful assessment of risk and benefit and under

strict medical supervision. Individuals with G6PD deficiency who are not able to take

primaquine should be retreated with chloroquine if relapses occur. The recommended

course of primaquine is 0.6 mg/kg daily for 14 days with a target total dose of > 6 mg/kg.

Failure of primaquine to eradicate hypnozoites is very unusual if this dose is attained.

However, in many cases adherence cannot be assured. If relapse occurs, the patient should

be retreated with chloroquine and primaquine. Primaquine should not be used during

pregnancy.

4.2 Summary

The patient is stated negative for malaria on 8 th October and primaquine is started 12th

October after G6PD screening was confirmed normal. It helps to prevent the parasites for

being dormant in the liver. This patient was discharged from the hospital after the clinical

condition was improved.

LITERATURE REFERRENCES

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