MALARIA 1.

04b
DATE: July 16, 2019
LECTURER: Dr. Maria Rafdora D. Conde, MD, MBA, FPCP INTERNAL MED

OUTLINE A. ETIOLOGY
 Six species of the genus Plasmodium causes nearly
I. Malaria Overview all malarial infections in humans:
a. Etiology and o P. falciparum
b. Pathogenesis
o P. vivax
c. Epidemiology
II. Pathophysiology o P. ovale (its two morphologically identical
a. Erythrocytic changes sympatric species—curtisi and wallikeri)
b. Host response o P. malariae
III. Clinical Features o P. knowlesi – monkey malaria parasite in
a. Severe Falciparum Malaria Southeast Asia
(Cerebral Malaria, Hypoglycemia, acidosis,
 Falciparum malaria – causes almost all deaths
Noncardiogeneic Pulmonary Edema, renal
Impairment, Hematologic Abnormalities,  P. knowlesi and P. vivax – can also cause severe
Liver dysfunction, Complications) illness
b. Malaria in Pregnancy B. PATHOGENESIS
c. Malaria in Children THE MALARIA TRANSMISSION CYCLE
d. Transfusion Malaria
IV. Chronic Complications of Malaria
a. Hyperreactive Malarial Splenomegaly 1. PRE-ERYTHROCYTIC (HEPATIC PHASE)
b. Quartan Malarial Nephropathy  Human infection begins when a female anopheline
V. Diagnosis
a. Demonstration of Parasite
mosquito inoculates plasmodial sporozoites from its
b. Lab findings of Acute Malaria salivary glands during a blood meal.
VI. Treatment  Sporozoites are microscopic motile forms of the
malaria parasite (infective stage to humans)
Legend:  These are carried rapidly via the bloodstream to the
liver (invade hepatic parenchymal cells, and begin a
To Remember/Trans
Lecturer Book Previous Trans period of asexual reproduction):
head note
o Intrahepatic or preerythrocytic schizogony – an
   ★ amplification process where a single sporozoite
may produce 10,000 t0 >30,000 daughter
merozoites in the liver.
(This is a book-based  transcription arranged by the team since
there was no formal lecture yet about the topic. Thank you.) o Note: For P. vivax and P. ovale infections: a
proportion of intrahepatic forms do not divide
I. MALARIA OVERVIEW immediately (hypnozoites) , but remain inert for
 protozoan disease transmitted by the bite of a period raging from 2 weeks to >1 year.
infected female Anopheles mosquitoes. o Hypnozoites are the dormant forms, which
 It is the most important parasitic disease in humans. causes the relapses that characterize infection
with the species.
 transmitted in 91 countries with three billion people,
and causes ~1,2o0 deaths each day  The swollen infected liver cells eventually burst,
discharging motile merozoites into the
 Over the past 15 years, mortality rates have
bloodstream.
decreased dramatically due to a highly effective
control programs in several countries.
 >50 years ago, it was eliminated from: US, Canada, 2. INTRA-ERYTHROCYTIC PHASE
Europe, and Russia.  These merozoites invade ERYTHROCYTES to
 An increasing number of countries are now become trophozoites
targeting malaria elimination, but this goal is  Multiply six- to twentyfold every 48h (P. knowlesi,
threatened by increasing resistance to antimalarial 24h; P. malaria, 72h).
drugs and insecticides. o The symptomatic stage of infection begins when
 Malaria remains today, as it has been for centuries, a the parasites reach densities of ~50/ μL of blood
heavy burden on tropical communities, a threat to (~100M parasites in the blood of an adult).
nonendemic countries, and a danger to travelers.
Intraerythrocytic Development
 During the first few hours, small “ring forms” of
different malaria species appear similar under light
microscopy.

EDITOR CHAN BARICAN, BAYAS, FABELLO 1 of 10

  Species-specific characteristics become evident as
the trophozoites enlarge.
 Hemozoin – malaria pigment that becomes visible
 The parasite assumes an irregular or ameboid shape.
 By the end of the intraerythrocytic life cycle, the
parasite has consumed 2/3 of the RBC’s hemoglobin,
and has grown to occupy most of the cell.
*Please refer appendix Figure 1. The malaria Transmission Cycle. Lifted from
 It is now called a schizont.
Harrison’s 20th ed.
o Intraerythrocytic Schizogony or Merogony
- “multiple nuclear divisions”
- The infected RBC then ruptures, and release
6-30 daughter merozoites, each potentially
capable of invading a new RBC and
repeating the cycle.
- infected RBC ruptures and release merozoite will either infect another
How the merozoites do invades RBCs?
 Erythrocyte Surface Receptors
o Attachment of merozoites to erythrocytes is mediated via a
complex interaction with several specific erythrocyte
surface receptors.
o P. falciparum merozoites binds to: Erythrocyte binding
antigen 175 and glycophorin A –
o Merozoite reticulocyte-binding protein homologue 5
(PfRh5) – plays a critical role binding to red cell basigin
(CD147, EMMPRIN).
o P. vivax binds to receptors on young red cells.
o Duffy blood-group antigen Fya or Fyb – plays an important
role in invasion.
o Most West Africans and people with origins in
that region carry the Duffy-negative FyFy
phenotype, and are generally resistant to P.
vivax malaria.
o P. knowlesi also invades Duffy-positive human
RBCs preferentially.
 Other Conditions that are resistant to Malarial infection:
-G6PD Deficiency, Sickle cell, HgS and C, Thalassemias
RBC Invasion and Destruction
 The disease in human beings is caused by the direct
effects of asexual parasite, and by the host’s
reaction.
 Some blood-stage parasites develop into
morphologically distinct, longer-lived sexual forms:
Gametocytes - transmit malaria to another
mosquitio during blood meal.
o In falciparum malaria, a delay of several
asexual cycles precedes this switch to
gametocytogenesis.
o Female gametocytes outnumber males
(4:1)
C. TRANSMISSION (man-mosquito)
 After ingestion in the blood meal of a biting female
anopheline mosquito, the male and female
gametocytes fuse to form a zygote in the insect’s
midgut.
o This zygote matures into an ookinete.
o Ookinete – penetrates and encysts in the
mosquito’s gut wall.
 The resulting oocyst expands by asexual division
until it bursts to liberate myriad motile sporozoites.
 These sporozoites migrate in the hemolymph to the
salivary gland of the mosquito to await inoculation
into another human at the next feed.
 This completes the life cycle.
LIFE CYCLE: (PARASITOLOGY REVIEW)
Mosquito injects SPOROZOITE to Man  travels the bloodstream and
infects the Liver (undergoes intrahepatic schizogony = MEROZOITES) 
busts hepatocytes and released to circulation merozoites invades RBC
and develops into TROPHOZOITES (Intraerythrocytic schizogony) 
RBC or develop into GAMETOCYTES once gametocytes are taken by
mosquito during blood meal, male and female gametes fuse and forms
ZYGOTEbecomes OOKINETE (gutOOCYSTruptures and
release SPOROZOITES that enters mosquito’s salivary gland- Mosquito
injects SPOROZOITE to Man
C. EPIDEMIOLOGY
Malaria occurs throughout most of the tropical regions of
The world.
o P. falciparum predominates in Africa, New Guinea,
and Hispaniola (i.e., the Dominican Republic and
Haiti)
o P. vivax is more common in Central and South
America
o P. falciparum and P. vivax are prevalent
approximately equal on the Indian subcontinent and
in eastern Asia and Oceania.
o P. malariae is found in most endemic areas, especially
throughout sub-Saharan Africa (less common)
o P. ovale is relatively unusual outside of Africa (<1% of
isolates)
o P. knowlesi causes human infections on the island of
Borneo, and elsewhere in Southeast Asia where main
hosts are long-tailed and pig-tailed macaques.
ENDEMICITY
 Endemicity has been defined in terms of rates of
microscopy-detected parasitemia or palpable
spleens in children (2-9 years old).
 It has been classified as:
o Hypoendemic (<10%)
o Mesoendemic (11-50%)
o Hyperendemic (51-75%)
o Holoendemic (>75%)
 In holo- and hyperendemic areas (certain regions of
tropical Africa or coastal New Guinea) with intense
P. falciparum transmission, people may sustain as
much as one infectious mosquito bite per day, and
are infected repeatedly throughout their lives.
 “Stable transmission” – constant, frequent, year-
round infection
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 o There may be an increased incidence of
symptomatic malaria during rainy season
(increased mosquito breeding and
transmission)
 “Unstable transmission” – low, erratic, or focal, full
protective immunity not acquired, and symptomatic
disease may occur at all ages.
o Exists in hypoendemic areas
EPIDEMICS
 Epidemics may occur when changes in
environmental, economic, or social conditions are
compounded by failure to incest in national
programs
 Also, by a breakdown in malaria control and
prevention services caused by war or civil disorder.
 It often results in high mortality rates among all age
groups.
PRINCIPAL DETERMINANTS OF THE EPIDEMIOLOGY
OF MALARIA
 These are the number (density), the human-biting
habits, and the longevity of the anopheline
mosquito vectors.
 More than 100 of the >400 anopheline species can
transmit malaria.
 The transmission of malaria is directly proportional
to:
1.) the density of the vector,
2.) the square of the number of human bites per day
per mosquito, and
3.)the tenth power of the probability of the
mosquito’s surviving for 1 day.
 Mosquito longevity is particularly important as a
determinant of malaria transmissibility.
o The portion of the parasite’s life cycle that
takes place within the mosquito—from
gametocyte ingestion to subsequent
inoculation (sporogony)—lasts 8-30 days,
depending on the ambient temperature.
o The mosquito must therefore survive for >7
days.
 Sporogony is not completed at cooler
temperatures—<16°C (<60.8°F) for P. vivax and
<21°C (<69.8°F) for P. falciparum. (Transmission does
not occur below these temperatures or at high
altitude)
o Malaria outbreaks and transmission have
occurred in the highlands (>1500 m) of
eastern Africa, which were previously free
of vectors.
 Anopheles gambiae species complex (Africa) are
the most effective mosquito vectors of malaria
o These are long-lived, occur in high densities
in tropical climates, breed readily, and bite
humans in preference to other animals
 Entomologic inoculation rate is the most common
measure of malaria transmission (i.e., no. of
sporozoite-positive mosquito bites per person per
year).
o <1 in some parts of Latin America and SEA
o >300 in parts of tropical Africa.
II. PATHOPHYSIOLOGY
A. ERYTHROCYTE CHANGES
 Invasion of erythrocytes  growing malarial
parasite progressively consumes and degrades
intracellular proteins—hemoglobin.
 Potentially toxic heme  detoxified by lipid-
mediated crystallization  biologically inert
hemozoin
 The parasite also alters the RBC membrane: changes
its transport properties, exposes cryptic surface
antigens, and inserts new parasite-derived proteins.
o RBC becomes more irregular in shape, more
antigenic, and less deformable
P. falciparum INFECTIONS
 Appearance of membrane protuberances on the
eyrthrocyte’s surface 12-15h after cell’s invasion
 “Knobs” extrude a high-molecular-weight,
antigenically variant, strain-specific erythrocyte
membrane adhesive protein (PfEMP1)
 PfeMP1 mediates attachment to receptors on venular
and capillary endothelium (cytoadherence).
 Vascular receptors:
o Intercellular adhesion molecule 1 and
endothelial protein C receptor – brain
o Chondroitin sulfate B – placenta
o CD36 – parasitized RBCs in most other
organs
 Erythrocytes with more mature parasites stick inside
 block capillaries and venules
 Infected RBCs may adhere to:
o uninfected RBCS  form rosettes; and
o to other parasitized erythrocytes 
agglutination
 Cytoadherence, resetting, and agglutination are
central to the pathogenesis of falciparum malaria.
o These result in the sequestration of
infected RBCs in vital organs (brain) 
interfere with microcirculatory flow and
metabolism
o Sequestered parasites develop out of reach
of the principal host defense mechanism:
splenic processing and filtration.
o As a consequence, only young ring forms of
asexual parasites are seen circulating in the
peripheral blood in falciparum malaria
o The level of peripheral parasitemia
underestimates the true number of
parasites within the body.
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  Severe malaria – associated with reduced
deformability of uninfected erythrocytes 
compromises passage through partially obstructed
capillaries and venules  shortens survival
OTHER HUMAN MALARIAS
 NO significant sequestration
 All stages of parasite’s development are seen on
peripheral-blood smears.
 P. vivax and P. ovale show a marked predeliction for
young RBCs; P. malariae for old cells
o These produces a level of parasitemia that
seldom exceeds 2%.
 P. falciparum invade erythrocytes of all ages, and
may be associated with very high parasite densities.
 P. knowlesi has shorter )24-h) asexual life cycle 
rapid increases  high parasite densities
*Please refer to appendix Table 1. Characteristics of Plasmodium Species
Infecting Humans.
B. HOST RESPONSE
 Activation of nonspecific defense mechanisms –
initial host response to malaria infection
 Splenic immunologic and filtrative clearance
functions are augmented.
 Removal of parasitized and uninfected erythrocytes
is accelerated.
 Pitting – spleen removes damaged ring-form
parasites; and returns once-infected erythrocytes to
the circulation (survival is shortened)
 When shizont ruptures, the parasitized cells
escaping splenic removal are destroyed
 Materials released upon splenic removal induces
monocyte/macrophage activation  release of
inflammatory cytokines  fever and other
pathologic effects
 >40ºC (>104ºF) damage mature parasites
o In untreated infections, effect of such
temperatures is to further synchronize the
parasitic cycle  eventual production of the
regular fever spikes and rigors 
characterization of different malarias
o Regular fever patterns are seldom seen
today due to prompt and effective
antimalarial treatment
FALCIPARUM MALARIA AND OTHER DISORDERS
 These genetic disorders confer protection against
death from falciparum malaria.
o HbA/S heterozygotes (sickle cell trait) –
have sixfold reduction risk of dying from
severe falciparum malaria, and are
correspondingly protected from bacterial
infections that complicate malaria
o Hemoglobin S-containing RBCs impair
parasite growth at low oxygen rensions
o P. falciparum-infected RBCs containing
hemoglobin S or C exhibit reduced
cytoadherence due to reduced surface
presentation of adhesin PfEMP1
o HbA/E heterozygotes have reduced
parasite multiplication at high parasite
densities
o Alpha-thalassemia patients have more
frequent malaria (both vivax and
falciparum) in the early years of life
(Melanesia)
o Melanesian ovalocytosis – rigid
erythrocytes resist merozoite invasion, and
intraerythrocytic melieu is hostile.
IMMUNITY
 Nonspecific host defense mechanisms – stop the
infection’s expansion
 Subsequent strain-specific immune response –
controls the infection
 Exposure to sufficient strains confer protection from
high-level parasitemia and diseases, but not from
infection.
 Premunition – a state of infection without illness
 Asymptomatic parasitemia – a result of
premunition
o Very common among adults and older
children living in regions with stable and
intense transmission, and also in parts of
low-transmission areas
o Parasitemia fluctuates in density but often
averages ~5000/mL
 Immunity is mainly specific for both species and
strain of infecting malarial parasite
 Humoral and cellular immunity
o An increase in serum levels of IgM, IgG, and
IgA are seen in immune individuals to limit
in vivo replication of the parasite.
o Surface adhesin (variant protein family
PfEMP1) – most important antigen in
falciparum malaria.
 Passively transferred IgG from immune adults –
reduce levels of parasitemia in children
 Passive transfer of maternal antibody contributes to
the partial protection of infants from severe malaria
in the first months of life.
 This complex immunity to disease declines when a
person lives outside an endemic area for several
months or longer.
FACTORS THAT RETARD THE DEVELOPMENT OF
CELLULAR IMMUNITY TO MALARIA
 Absence of major histocompatibility antigens of the
surface of infected RBCs results to:
o Precluded direct T cell antigens recognition
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 o Malaria antigen-specific immune
unresponsiveness
o Enormous strain diversity of malarial
parasites
 If treatment is not given, Parasites may persist in the
blood for months or years (for decades in P.
malariae).
 Complexity of immune response in malaria,
sophistication of parasites’ evasion mechanisms,
and lack of good in vitro correlate with clinical
immunity have all slowed progress toward an
effective vaccine.

III. CLINICAL FEATURES

 Malaria is a common cause of fever in tropical
countries.
 The first symptoms of malaria are nonspecific:
o lack of a sense of well-being;
o headache;
o fatigue;
o abdominal discomfort; and
o muscle aches followed by fever
o these all similar to the symptoms of a minor
viral illness.
o Nausea, vomiting, and orthostatic
hypotension are common.
 The classic malarial paroxysms, in which fever
spikes, chills, and rigors occur at regular intervals,
Table 2. Major manifestations of severe falciparum malaria
are relatively unusual and suggest infection (often
relapse) with P. vivax or P. ovale.
COMPLICATIONS OF SEVERE FALCIPARUM MALARIA
 The fever is usually irregular at first (that of
A. CEREBRAL MALARIA
falciparum malaria may never become regular).
o The temperature of nonimmune  Coma – characteristic and ominous feature of
individuals and children often rises above falciparum malaria.
40°C (104°F), with accompanying o It has been associated with death rates of
tachycardia and sometimes delirium. ~20% among adults and 15% among
 Generalized seizures are associated specifically children.
with falciparum malaria and may herald the  manifests as diffuse symmetric encephalopathy
development of encephalopathy (cerebral malaria). o passive resistance to head flexion may be
 Frequent vivax relapse is an important cause of detected
anemia in young children in some areas. o eyes may be divergent, and bruxism and a
 Slight enlargement of the liver is also common, pout reflex are common
particularly among young children. o muscle tone may be either increased or
 Mild jaundice is common among adults. decreased.
o flexor or extensor posturing may be seen
o on routine funduscopy, ~15% of patients
SEVERE FALCIPARUM MALARIA
have retinal hemorrhages; with pupillary
 Uncomplicated falciparum malaria (i.e., that in
dilation and indirect ophthalmoscopy.
which the patient can sit or stand unaided and can
 Convulsions occur in ~10% of adults and up to 50%
swallow medicines and food) carries a mortality
of children with cerebral malaria.
rate of <0.1%.
o More covert seizure activity is common,
 Once vital-organ dysfunction occurs or the total
particularly among children, and may
proportion of erythrocytes infected increases to
manifest as repetitive tonic–clonic eye
>2% (a level corresponding to >1012 parasites in an
movements or even hypersalivation.
adult), mortality risk rises steeply, depending on
o Hemiplegia, cerebral palsy, cortical
the immunity of the host.
blindness, deafness, and impaired cognition
may all occur.

1.04b MALARIA 5 of 14
 Persistent language deficit may be seen in ~10% of
children surviving cerebral malaria have a
o There may also be deficits in learning,
planning and executive functions, attention,
memory, and nonverbal functioning.
 The incidence of epilepsy is increased and life
expectancy decreased among these children.
B. HYPOGLYCEMIA
 Important and common complication among
children and pregnant women in severe malaria.
 Results from a failure of hepatic gluconeogenesis
and an increase in the consumption of glucose by
both the host and the malaria parasites.
 Quinine – a powerful stimulant of pancreatic insulin
secretion, which is still widely used for the
treatment of both severe and uncomplicated
falciparum malaria.
C. ACIDOSIS
 Acidosis – an important cause of death from severe
malaria; results from accumulation of organic acids.
 Hydroxyphenyllactic acid, α-hydroxybutyric acid,
and β-hydroxybutyric acid concentrations are
elevated.
 Acidotic breathing, sometimes called “respiratory
distress,” is a sign of poor prognosis.
 Lactic acidosis – caused by the combination of
anaerobic glycolysis in tissues where sequestered
parasites interfere with microcirculatory flow,
lactate production by the parasites, and a failure of
hepatic and renal lactate clearance.
D. NONCARDIOGENIC PULMONARY EDEMA
 Noncardiogenic pulmonary edema may develop in
adults with severe falciparum malaria, even after
several days of antimalarial therapy.
 The pathogenesis of this variant of the adult
respiratory distress syndrome is unclear. The
mortality rate is >80%.
E. RENAL IMPAIRMENT
 Acute kidney injury is common in severe falciparum
malaria.
 Related to erythrocyte sequestration and
agglutination interfering with renal microcirculatory
flow and metabolism.
 Clinically and pathologically, this syndrome
manifests as acute tubular necrosis.
F. HEMATOLOGIC ABNORMALITIES
 Anemia results from accelerated RBC removal by
the spleen, obligatory RBC destruction at parasite
schizogony, and ineffective erythropoiesis.
 In severe malaria, the deformability of both infected
and uninfected RBCs is reduced.
 The degree of reduced deformability correlates with
prognosis and with the development of anemia.
Splenic clearance of all RBCs is increased.
 Acute hemolytic anemia with massive
hemoglobinuria (“blackwater fever”) may occur.
Hemoglobinuria may contribute to renal injury.
G. LIVER DYSFUNCTION
 Mild hemolytic jaundice is common in malaria.
 Severe jaundice is associated with P. falciparum
infections
o more common among adults than among
children;
 Due to hemolysis, hepatocyte injury, and
cholestasis.
H. OTHER COMPLICATIONS
 Malaria anemia is worsened by concurrent infections
with intestinal helminths, hookworm.
 Septicemia may complicate severe malaria,
particularly in children.
Table 3. Frequencies of complications of severe falciparum malaria
MALARIA IN PREGNANCY
 Malaria in early pregnancy causes fetal loss.
 In areas of high malaria transmission, falciparum
malaria in primi- and secundigravid women is
associated with low birth weight (average reduction,
~170 g) and consequently increased infant mortality
rates.
 In areas with unstable transmission of malaria,
pregnant women are prone to severe infections and
are particularly likely to develop high parasitemias
with anemia, hypoglycemia, and acute pulmonary
edema.
 Fetal distress, premature labor, and stillbirth or low
birth weight are common results.

MALARIA IN CHILDREN
 Most of the estimated 445,000 deaths from
falciparum malaria each year are in young African
children.
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  Convulsions, coma, hypoglycemia, metabolic
acidosis, and severe anemia are relatively common
among children with severe malaria.
TRANSFUSION MALARIA
 Malaria can be transmitted by blood transfusion,
needlestick injury, or organ transplantation.
 The incubation period in these settings is often short
because there is no preerythrocytic stage of
development.
IV. CHRONIC COMPLICATIONS OF MALARIA
HYPERREACTIVE MALARIAL SPLENOMEGALY
 Chronic or repeated malarial infections produce
hypergammaglobulinemia; normochromic,
normocytic anemia; splenomegaly.
 Some residents of malaria-endemic areas in tropical
countries exhibit an abnormal immunologic
response to repeated infections characterized by:
o massive splenomegaly,
o hepatomegaly,
o marked elevations in serum IgM and
o malarial antibody titers, hepatic sinusoidal
lymphocytosis,
o and (in Africa) peripheral B cell
lymphocytosis.
 This syndrome has been associated with the
production of cytotoxic IgM antibodies to CD8+ T
lymphocytes, antibodies to CD5+ T lymphocytes,
and an increase in the ratio of CD4+ to CD8+ T
cells.
 These events may lead to uninhibited B cell
production of IgM and the formation of
cryoglobulins (IgM aggregates and immune
complexes).
 This immunologic process stimulates lymphoid
hyperplasia and clearance activity and eventually
produces splenomegaly.
QUARTAN MALARIAL NEPHROPATHY
 Chronic or repeated infections with P. malariae (and
possibly with other malarial species) may cause
soluble immune complex injury to the renal
glomeruli, resulting in the nephrotic syndrome.
BURKITT’S LYMPHOMA AND EPSTEIN- BARR VIRUS
INFECTION
 It is possible that malaria-related immune
dysregulation provokes infection with lymphoma
viruses.
 Burkitt’s lymphoma is strongly associated with
Epstein-Barr virus.
 The prevalence of this childhood tumor is high in
high-malaria-transmission areas of Africa.
V. DIAGNOSIS
 Thick and thin blood smears: should be prepared
and examined immediately to confirm the diagnosis
and identify the species of infecting parasite.
o If negative (when examined by an
experienced microscopist), the patient does
not have malaria.
A. DEMONSTRATION OF PARASITE
 The diagnosis of malaria rests on the
demonstration of asexual forms of the parasite in
stained peripheral-blood smears
 Staining of parasites with the fluorescent dye
acridine orange allows more rapid diagnosis of
malaria (but not speciation of the infection) in
patients with low-level parasitemia.
This is a Parasitology topic but you can refer to the last part of appendix for the
demonstration of parasite. :-)
THIN BLOOD SMEAR
 air-dried, fixed in anhydrous methanol, and stained
 RBCs in the tail of the film should then be examined
under oil immersion (×1000 magnification).
THICK BLOOD SMEAR
 uneven thickness; dried thoroughly and stained
without fixing
 Has the advantage of concentrating the parasites
(by 40- to 100-fold compared with a thin blood film)
and thus increasing diagnostic sensitivity
 Before a thick smear is judged to be negative, 100–
200 fields should be examined
Estimating Degree of Parasitemia
 Thin Smear: Expressed as the number of
parasitized erythrocytes per 1000 RBCs.
 Thick Smear: Both parasites and white blood cells
(WBCs) are counted, and the number of parasites
per unit volume is calculated from the total
leukocyte count. Alternatively, a WBC count of
8000/μL is assumed. This figure is converted to the
number of parasitized erythrocytes per microliter. A
minimum of 200 WBCs should be counted under oil
immersion.
 In high-transmission areas, the presence of up to
10,000 parasites/µL of blood may be tolerated
without symptoms or signs in partially immune
individuals
o Detection of low-density malaria
parasitemia is sensitive but has low
specificity in identifying malaria as the
cause of illness.
o Low-density parasitemia is a common
incidental finding in other conditions
causing fever.
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ANTIBODY-BASED DIAGNOTIC TESTS
 Rapid, simple, sensitive, and specific antibody-based
diagnostic stick or card tests that detect P.
falciparum–specific, histidine-rich protein 2 (PfHRP2),
lactate dehydrogenase, or aldolase antigens in
finger-prick blood samples are now being used
widely in control programs.
 A disadvantage of rapid tests is that they do not
quantify parasitemia.
*Please refer to appendix Table 4. Standard Methods for the Diagnosis of
Malaria. Lifted from Harrison’s 20th ed.
Parasite Density and Prognosis
 In general, patients with >105 parasites/μL are at
increased risk of dying.
 In severe malaria, poor prognosis is indicated by a
predominance of more mature P. falciparum
parasites (i.e., >20% of parasites with visible
pigment) in the peripheral-blood film or by the
presence of phagocytosed malarial pigment in >5%
of neutrophils (an indicator of recent schizogony).
o Phagocytosed malarial pigment seen inside
peripheral-blood monocytes may provide a
clue to recent infection if malaria parasites
are not detectable.
POLYMERACE CHAIN REACTION (PCR)
 More sensitive than microscopy or rapid diagnostic
tests for detecting malaria parasites and defining
malarial species.
 Used in reference centers in endemic areas but
impractical in standard clinical setting.
 Useful in identifying asymptomatic infections as
control and eradication programs drive parasite
prevalences down to very low levels.
SEROLOGIC DIAGNOSIS
With either indirect fluorescent antibody or enzyme-linked
immunosorbent assays,
 Useful for screening of prospective blood donors
 Useful as a measure of transmission intensity in
future epidemiologic studies
 Has no place in the diagnosis of acute illness
B. LABORATORY FINDINGS IN ACUTE MALARIA
 Normochromic, normocytic anemia, is usual
 Leukocyte count is generally normal (may be raised
in very severe infections)
 In the weeks after acute infection, there is slight
monocytosis, lymphopenia, and eosinopenia, with
reactive lymphocytosis and eosinophilia
 Platelet count is usually reduced to ~105/μL
 The erythrocyte sedimentation rate, plasma
viscosity, and levels of C-reactive protein and other
acute-phase proteins are elevated
 Severe infections may be accompanied by
prolonged prothrombin and partial thromboplastin
times and by more severe thrombocytopenia.
o Antithrombin III levels are reduced even in
mild infection
 In severe malaria, may include metabolic acidosis,
with low plasma concentrations of glucose, sodium,
bicarbonate, phosphate, and albumin, together with
elevations in lactate, BUN, creatinine, urate, muscle
and liver enzymes, and conjugated and
unconjugated bilirubin
 Hypergammaglobulinemia is usual in immune and
semi-immune subjects living in malaria-endemic
areas
 In adults and children with cerebral malaria, the
mean cerebrospinal fluid (CSF) opening pressure at
lumbar puncture is ~160mm H2O; usually the CSF
content is normal or there is a slight elevation of
total protein level (<1.0 g/L [<100 mg/dL]) and cell
count (<20/μL)
VI. TREATMENT and MANAGEMENTS
 Patients with severe malaria and those unable to
take oral drugs should receive parenteral
antimalarial therapy immediately.
 The World Health Organization (WHO) recommends
artemisinin based combination therapy (ACT) as
first-line treatment for uncomplicated falciparum
malaria in malaria-endemic areas and for P. knowlesi
infections.
Please refer to appendix Table 5 and65.
A. SEVERE MALARIA
 Artesunate is now the drug of choice for all px with
severe malaria everywhere
o Given by IV injection but is also absorbed
rapidly following IM injection
o Pre-referral administration of rectal
artesunate has been shown to decrease
mortality rates among severely ill children
o Does not require dose adjustments in liver
dysfunction or renal failure
o Should be used in pregnant women with
severe malaria
 Parenteral quinidine is potentially dangerous and
must be closely monitored if dysrhythmias and
hypotension are to be avoided.
o If total plasma levels exceed 8 μg/mL, if the
QTc interval exceeds 0.6 s, or if the QRS
complex widens by more than 25% over
baseline, then infusion rates should be
slowed or infusion stopped temporarily.
1.04b MALARIA 8 of 14
 o If arrhythmia or saline-unresponsive
hypotension develops, treatment with this
drug should be discontinued.
 Quinine is safer than quinidine.
o Total plasma concentrations of 8–15 mg/L
for quinine and 3.5–8.0 mg/L for quinidine
are effective and do not cause serious
toxicity.
 Severe falciparum malaria constitutes a medical
emergency requiring intensive nursing care and
careful management.
 Adjunctive treatments such as high-dose
glucocorticoids, urea, heparin, dextran,
desferrioxamine, antibody to tumor necrosis factor
α, high-dose phenobarbital (20 mg/kg), mannitol, or
large-volume fluid or albumin boluses have proved
either ineffective or harmful in clinical trials and
should not be used.
 Acute renal failure or severe metabolic acidosis:
hemofiltration or hemodialysis should be started
as early as possible.
o If the patient remains seriously ill or in
acute renal failure for >2 days, maintenance
doses of quinine or quinidine should be
reduced by 30–50% to prevent toxic
accumulation of the drug.
o If safe and feasible, exchange transfusion
may be considered
 Convulsions : IV (or rectal) benzodiazepines
 If respiratory support is not available, a full
loading dose of phenobarbital (20 mg/kg)
to prevent convulsions should NOT be
given as it may cause respiratory arrest.
 Nasogastric feeding should be delayed in
nonintubated patients (for 60 h in adults and 36 h in
children) to reduce the risk of aspiration pneumonia
o As soon as the patient can take fluids, oral
therapy should be substituted for
parenteral treatment and a full 3-day
course of ACT given.
 Mefloquine should be avoided as follow-on
treatment for severe malaria because of the
increased risk of post-malaria neurologic syndrome.
B. UNCOMPLICATED MALARIA
 P. falciparum and P. knowlesi infections should be
treated with an artemisinin-based combination.
 P. vivax, P. malariae, and P. ovale should be treated
with an artemisinin-based combination or oral
chloroquine (total dose, 25 mg of base/kg).
 Five ACT regimens are currently recommended by
the WHO: artemether-lumefantrine, artesunate-
mefloquine, dihydroartemisinin-piperaquine,
artesunate-sulfadoxine-pyrimethamine, and
artesunate-amodiaquine.
 There is increasing evidence for both the efficacy
and the safety of artesunate-pyronaridine.
 In areas of low malaria transmission, a single dose
of primaquine (0.25 mg/kg) should be added to
ACT as a P. falciparum gametocytocide to reduce
the transmissibility of the infection.
o This low dose of primaquine is safe even in
G6PD deficiency
 Can be given in a dose of 0.75 mg
of base/kg (maximum, 45 mg)
once weekly for 8 weeks (if mild
G6PD).
o Pregnant women should NOT be given
primaquine but should receive suppressive
prophylaxis with chloroquine (5 mg of
base/kg per week) until delivery, after
which radical treatment can be given.
 Atovaquone-proguanil is highly effective
everywhere, although it is seldom used in endemic
areas because of its high cost and the propensity for
rapid emergence of resistance.
 Threat: Emergence of artemisinin-resistant P.
falciparum in the Greater Mekong subregion of
Southeast Asia.
o Infections with these parasites are cleared
slowly from the blood, with clearance times
typically exceeding 3 days, and cure rates
with ACT have fallen to unacceptably low
levels in some areas.
 The 3-day ACT regimens are all well tolerated,
although mefloquine is associated with increased
rates of vomiting and dizziness.
 Another alternative is a 7-day course of either
artesunate or quinine plus tetracycline, doxycycline,
or clindamycin. Clinical responses are slower than
those following ACT.
 Tetracycline and doxycycline cannot be given to
pregnant women after 15 weeks of gestation or to
children <8 years of age.
 Oral quinine is extremely bitter and regularly
produces cinchonism comprising tinnitus, high-tone
deafness, nausea, vomiting, and dysphoria.
Adherence is poor with the required 7-day regimens.
 Patients should be monitored for vomiting
for 1 h after the administration of any oral
antimalarial drug
o If there is vomiting, the dose should be
repeated.
 All the antimalarial quinolines (chloroquine,
mefloquine, and quinine) exacerbate the orthostatic
hypotension associated with malaria, and all are
tolerated better by children than by adults.
 Thick blood films should be checked again 1 and 2
days later to exclude the diagnosis.
o Nonimmune patients receiving treatment
for malaria should have daily parasite
counts performed until the thick films are
negative.
1.04b MALARIA 9 of 14
 o If the level of parasitemia does not fall CASE
below 25% of the admission value in 72 h or A 25- year-old female complained of 5 day history of fever and
if parasitemia has not cleared by 7 days headache which usually occurs in the morning, associated with
(and adherence is assured), drug resistance chills ,photophobia, vomiting and anorexia. The fever would
is likely and the regimen should be resolve in the afternoon.
changed.
 To eradicate persistent liver stages and prevent References
relapse (radical treatment), primaquine (0.5 mg of  Dra Conde’s Powerpoint
base/kg in East Asia and Oceania and 0.25 mg/kg  Harrison’s 20E
elsewhere) should be given once daily for 14 days to
patients with P. vivax or P. ovale infection after
laboratory tests for G6PD deficiency have proved
negative.

C. MANAGEMENT OF COMPLICATIONS
Acute Renal Failure
 Fluid administration should be restricted to prevent
volume overload
o If plasma levels of BUN or creatinine rise
despite adequate rehydration
 Renal replacement therapy is best performed early
 Hemofiltration and hemodialysis are more effective
than peritoneal dialysis and are associated with
lower mortality risk.

Acute Pulmonary Edema

(Acute Respiratory Distress Syndrome)
 Patients should be positioned with the head of the
bed at a 45° elevation and should be given oxygen
and IV diuretics.
 Positive-pressure ventilation should be started early
if the immediate measures fail.
 Rarely, patients may require extracorporeal
membrane oxygenation.

Hypoglycemia
 An initial slow injection of 20% dextrose (2 mL/kg
over 10 min)
o Should be followed by an infusion of 10%
dextrose (0.10 g/kg per hour)
Sepsis
 Antibiotics should be considered for severely ill
patients of any age who are not responding to
antimalarial treatment.
Other Complications
 Patients who develop spontaneous bleeding should
be given fresh blood and IV vitamin K.
 Aspiration pneumonia should be suspected in any
unconscious patient with convulsions, particularly
with persistent hyperventilation; IV antimicrobial
agents and oxygen should be administered, and
pulmonary toilet should be undertaken

1.04b MALARIA 10 of 14
 SUMMARY/APPENDIX

Table 1. Characteristics of Plasmodium Species Infecting Humans. Lifted from Harrison’s 20th ed.

Figure 1. The malaria Transmission Cycle. Lifted from Harrison’s 20th ed.

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Table4. Standard Methods for the Diagnosis of Malaria. Lifted from Harrison’s 20th ed.

Table 5. Regimens for the Treatment of Malaria. Lifted from Harrison’s 20th ed.

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Table 6. Properties of Antimalarial Drugs. Lifted from Harrison’s 20th ed.

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DEMONSTRATIONS OF PARASITES (for clearer picture please
refer to Harrison’s pg. 1581-1582)

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