Malaria- means bad air

MALARIA

ETIOLOGY

A protozoan disease caused by sporozoa of

genus Plasmodium
Transmitted by a bite of an infected female
Anopheles mosquito
Infective stage to man: Sporozoites

4 Spp. of Plasmodium that affect man:

1. Plasmodium falciparum
found in the
2. Plasmodium vivax
Phils.
3. Plasmodium ovale
4. Plasmodium malariae
Almost all deaths are caused by falciparum
malaria.

LIFE CYCLE

patterned from Harrisons

Asexual Pre-Erythrocytic Stage

The oocyst expands by asexual division until it

bursts to liberate myriad motile sporozoites w/c
migrate in the hemolymph to the slivary gland of
the mosquito to await inoculation into another
human at the next feeding.
Pre-erythrocytic cycle
- invasion of RBC
Intra-erythrocytic cycle
- Disease manifestation- direct toxic effect in RBCrelated waste products that stimulate
macrophages to produce pro-inflammatory
cytokines
Asexual Cycle/Schizogony
- occurs in man; man serves only as the
intermediate host
- Infective stage to man: sporozoite
Sexual Cycle/Sporogony/Gametogony
- occurs in the mosquito; mosquito is the final host
of the
parasite
- Infective stage to mosquito: gametocytes
(macrogamete: pertains to female gametocyte;
microgamete: male)
EPIDEMIOLOGY

Female Anopheline mosquito inoculates plasmodial

sporozoites from its salivary gland.

Sporozoites are carried rapidly via the

bloodstream to the liver, invading hepatic
parenchymal cells.

Swollen infected liver cells eventually burst

discharging motile merozoites into the
bloodstream.

Falciparum and ovale malaria are tropical

diseases.
P. falciparum predominates in Africa, New
Guinea, and Haiti; P. vivax is more common in
Central America;
P. malariae in sub-saharan Africa; P.ovale in
Africa

Principal Determinants of Epidemiology in

Malaria:
1.) Number (density) transmission of malaria is
directly
proportional to the density of the vector.
2.) Human-biting habits
3.) Longevity of the Anopheline Vectors: to
transmit malaria, mosquito must survive >7
days considering that the parasites life cycle
lasts from 8-30 days.
Sickle Cell disease - can serve as protection
from falciparum infection. On low O2 tension,
RBCs develop aggregates that are needle-like
that will pierce the parasite.
FYa and FYb genes that express receptors for
RBC. When certain people dont have these
genes or are FY-; this can serve as protection
from vivax infection.

In P.vivax and P.ovale infections, the

intrahepatic forms do not divide immediately
but remain dormant, as hypnozoites, for
3weeks or longer causing relapses.

Asexual Erythrocytic Stage

Merozoites invade RBCs and multiply six- to
twenty fold every 48-72 hours and become
trophozoites.
Trophozoites enlarge, species-specific chars
become evident, pigment becomes visible,
parasite assumes an amoeboid shape
consuming nearly all hemoglobin and grown
to occupy most of the RBC as schizont.

PATHOGENESIS

Some of the parasites develop into

morphologically distinct, longer-lived sexual
forms (gametocytes) that can transmit
malaria.

How does malaria cause disease? TISSUE

HYPOXIA (underlying basis): lowered O2
tension in tissues hypoxia/anoxia of
tissues

Sexual Erythrocytic Stage

After being ingested in the blood meal of a biting

female anopheline mosquito, the male and
female gametocytes form a zygote in the
insects midgut.
The zygote matures into an ookinete which
penetrates the mosquitos gut wall forming an
oocyst.

Cerebral malaria: causes gray discoloration of

the white matter due to hemozoin pigment;
constricted ventricles due to cerebral edema

ERYTHROCYTE CHANGES IN MALARIA CAUSING

TISSUE HYPOXIA
1. Sequestration
- after invading the erythrocytes, the growing malarial
parasite progressively consumes and degrades
intracellular proteins principally hemoglobin.

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- the parasite also alters the RBC membrane by

DEFINITION OF SEVERE MALARIA AND
COMPLICATED FALCIPARUM MALARIA
changing its transport properties, exposing cryptic
surfaces antigens, and inserting new parasite-derived
proteins.
2. Cytoadherence
- In P.falciparum infection, membrane protruberances
appear on the RBCs surface; these knobs extrude a
high molecular weight, antigenically variant, strain
specific PfEMP1 (P. falciparum erythrocyte membrane
protein 1) that mediates attachment to receptors on
venular and capillary endothelium.
3. Rosetting
- P.falciparum infected RBCs adhere to non-infected
RBCs forming rosettes or to other parasitized RBCs
causing agglutination.
4. Reduced Red Cell Deformability
- severe malaria compromises passage of RBCs
through partially obstructed capillaries and venules
and shortens RBC survival.
- RBC diameter is reduced to 4um (Normal: 6-8um)

Blackwater fever, especially in P. falciparum

infections; characterized by intravascular
hemolysis
with
hemoglobinemia
and
hemoglobinuria.

1.
2.

Cerebral malaria
Severe anemia (hematocrit <15%)
results from accelerated RBC removal by the
spleen, obligatory RBC destruction, and
ineffective erythropoiesis
Renal failure (no urine output <400mL in 24 h,
or 12mL/kg/24 h after rehydration, or serum
creatinine > 3 mg%)
related to RBC sequestration interfering with
renal microcirculatory flow and metabolism
acute tubular necrosis
Pulmonary edema or adult respiratory distress
syndrome
Hypoglycemia (blood sugar <40 mg%)
results from a failure of heptic gluconeogenesis
and increase in consumption of glucose by the
host and the parasite
Shock (systolic BP<70 mmHg in adults or <50
mmHg in children age 1-5 y)

3.

4.
5.

6.

Hemoglobinopathies Protecting The Host From

Infection by Malarial Parasites

1) Sickle Cell Trait (HbA/S Heterozygotes)

have a six-fold reduction in the risk of dying from
severe falciparum malaria due to impaired parasite
growth at low oxygen tensions and aggregates of
needle-like structures that pirces the parasite
2) Alpha Thalassemia in children
3) Melanesian Ovalocytosis
-rigid erythrocytes resist merozoite invasion and
intraerythrocytic milieu is hostile.
4) Duffy Blood Group System (FY a-b-)
individuals with this blood group system are protected
from having P.vivax infection.
CLINICAL MANIFESTATIONS

first manifestations are non-specific: the lack of a

sense of well-being, headache, fatigue, abdominal
discomfort, and muscle aches, followed by fever.
1. Tertian malaria (fever every third day) for P.
vivax and p. ovale
2. Quartan malaria (fever every fourth day) for
P. malariae
3. Subtertian malaria, or sometimes called
malignant tertian (fever more often than every
third day, and the disease is lethal) for P.
METHODS FOR THE DIAGNOSIS OF MALARIA
4.

Most

falciparum
Malignant Tertian malaria for P. falciparum
This qualification of malaria is no longer
applicable nowadays.
characteristic pathologic feature/s:
Anemia (P. falciparum produces greatest
degree of anemia) that is microcytic
hypochromic type due to direct loss (impaired
hematopoiesis) or destruction (by parasite) of
RBCs.
Pigmentation of organs (phagocytosis of
hemozoin or malarial pigment after the rupture
of host cells, macrophages of spleen & bone
marrow; Kupffer cells of liver, at termination of
asexual cycle) that increases as infection
lengthens. Evident grossly in chronic malaria
Liver enlargement due to congestion in
acute malaria and increases in size during
chronic malaria.
Splenomegaly is evident, first as a result of
congestion following cavernous dilatation of
sinusoids and then results from increase in
macrophage elements in Billroths cords.
Repeated attacks results to progressively
greater enlargement. Palpation of the spleen is
characteristic of malaria.

7.
8.
9.
10.
11.
12.

13.

Spontaneous
bleeding
and
disseminated
intravascular coagulation
Repeated convulsions
Acidosis (arterial pH<7.25 or plasma HCO3<15)
Macroscopic hemoglobinuria
Hyperparasitemia
(>5%
parasitemia
in
nonimmunes)
Hepatic dysfunction
common manifestation is jaundice
Hyperpyrexia (T>40 OC)

Microscopy (Gold Standard)

-Thick blood film for rapid detection of parasite
-Thin blood film for species identification
-Giemsa stain is used
Serological tests
a) PfHRP2 (P.falciparum histidine rich protein 2)
dipstick or
card test
b) Plasmodium LDH dipstick or card test
Microtube concentration methods with acridine
orange testing
-examined under Fluorescent Microscopes

Plasmodium falciparum:

Early trophozoites-small rings about 1/5 th diameter

of RBC, have 2 nuclear chromatin dots that may
also lie on opposite side of ring or close together.
Marginal or accole forms have rings at margins of
RBC that is diagnostic and more common; multiple
ring invasion of RBC may also be evident but less
common.

Late trophozoites-not found in PBS because P. f.

leaves blood circulation when trophozoites are
large. When present (in moribund px) they show
rings of larger size. Infected erythrocytes show
Maurers dots (coarse pink staining on RBC).

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Schizont-in internal organs but rarely appears in

PBS. Parasite filling erythrocytes with no increase in
size. With 10-20 merozoites, dark staining malaria
pigments and few Maurers dots.
Gametocyte-shaped like a sausage (a.k.a crescent)
that is diagnostic of the sp., seen in PBS.
Males/microgametocytes has larger nucleus and
pale blue cytoplasm in w/c blackish-brown pigment
of
parasite
is
distributed;
females/macrogametocytes has smaller, more
compact nucleus and a dark blue cytoplasm with
pigment collected together around nucleus.

Vivax/ ovale with RBC predilection;

infects young RBCs

Malariae infects old/senescent RBCs

Falciparum infects all RBCs

Plasmodium vivax:

Early trophozoite-stout rings, 1/3 rd the diameter of

RBC. Show 1 chromatin dot.

Late trophozoite-irregular and amoeboid with

pseudopodial processes. Larger with fine grains of
brown pigment inside. RBC is enlarged and with
characteristic red stippling or Schuffners dot.

ANG DAMING DOTS.. MERON PA SA SUSUNOD

Schizont-same size as normal RBC. Nucleus is

divided into 18-24 merozoites that are arranged in
a morula formation (like cluster of grapes).
Pigement is collected in a clump in the center of
morula. RBC is enlraged and pale and with
Schuffners dot.

Gametocyte-full-blown if round and occupies most

of enlarged RBC. Malaria pigment is scattered
throughout the cytoplasm. Differentiation of sex is
not easy and these appear in PBS in early infection.

Plasmodium malariae

Early trophozoite-large stout ring 1/3rd of diameter

of RBC. Multiple infection of RBC is common. Some
parasite may show coarse granular golden-yellow
pigment that is characteristic of P.m.

Late
trophozoite-more
solid
looking
than
corresponding stage of P. vivax. Assumes a
characteristic band from across the diameter of the
RBC. Band can be wide or narrow but well-defined
and is diagnostic for this sp. Pigment is coarser and
with golden-yellow and black pigment (Ziemanns
dots). Infected RBC is of normal size.

Schizont-nearly fills the RBC and with 6-12

merozoites that form characteristic rosette in the
center where the coarse pigment is collected into
dense black clump. RBC still not enlarged.

Gametocyte-round, occupying most infected RBC

(not enlarged). Coarse black pigment is scattered
throughout. Nucleus and cytoplasm are undivided.
Male and female are not easy to differentiate.
These appear in PBS early in the infection.

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Typhoid fever - muscles are not tender in

malaria
Urinary tract infection
Yellow fever

Plasmodium ovale:

Ealry trophozoite-about 2-2.5 um in diameter.

Resembles more closely than that of P. malariae
but band is not seen. Pigment granules are coarse
and dark brown in color but scanty. Infected RBC
shows granules like Schuffers dots with violet tinge
called James dots. Infected RBC slightly enlarged,
pale, often oval with fimbriated edges.

Late
trophozoites-solid-looking
non-ameboid
parasites. Pigment is scanty and James dots are
seen.

Schizont-with 4-12 merozoites (ave. 8) in primary

attack, nearly increasing to 12-18 in relapses.
Nearly fills RBC, oval in shape. With James dots.

Gametocyte-indistinguishable from P. malariae.

Round and fills the RBC when mature.

DIFFERENTIAL DIAGNOSIS OF SEVERE

FALCIPARUM MALARIA
Enteric fever, brucellosis,
Fever
influenza
Hyperpyrexia
Heat stroke, sepsis
Viral hepatitis, leptospirosis,
Jaundice
relapsing fevers, yellow
fever, drug-induced or toxic
hepatitis
Severe septicemia, liver
Hypoglycemia
failure, Reyes syndrome
Drug-induced, due to toxic
substances, autoimmune
Acute hemolytic anemia
diseases, blood diseases
e.g. inheritable red cell
abnormalities, or G6PD
deficiency
Gastrointestinal
Peptic ulcer, gastroenteritis,
symptoms
salmonellosis, travelers
diarrhea
Hepatitis failure, poisons,
Abnormal bleeding
viral hemorrhagic fevers,
leptospirosis
Convulsions
Febrile confusions, epilepsy,
cerebrovascular accidents
Viral , fungal, bacterial
Encephalopathy
protozoal encephalitis;
eclampsia, toxic substances
COMPLICATIONS
Hyperthermia
Acute Pulmonary Edema
Acute Renal Failure
Hepatic Dysfunction
Hypoglycemia
Shock (Algid Malaria)
Severe Anemia
Metabolic Acidosis
Hyperparasitemia
TREATMENT
Drug of Choice according to WHO
- Quinine: induces devt of resistance by the
parasite so it is replaced by a combination of
Quinine and Tetra/Doxy/Aminocycline.
Artemesinin combined with Mefloquine: highly
effective
for P. falciparum
Mefloquine: for prophylaxis; taken 4 weeks
before travel
Vibromycin(100 mg): can be taken on short
notice

Differential Diagnosis:

Babesiosis

Hepatitis

Influenza

Liver abscess

Meningitis absence of neck stiffness and

photophobia in malaria

Tuberculosis

For schizonts

Sulfonamides (Folic Acid synth)

Chlorguanide, pyrimethamine, colchicine (Folic

Acid Metab)

Quinine, Chloroquine, amodiaquine (Nucleic

Acid Metab)
For gametocytes

Primaquin
For Exo-erythrocytic cycles

Chlorguanide,
pyrimethamine
(Folic
Acid
Metab)

Primaquin

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DRUGS USED FOR MALARIAL DISEASES

P. falciparum
A. Chloroquinesensitive
B. Chloroquineresistant
but sensitive to
sulfadoxine/
pyrimethamine
C. Chloroquineresistant
and resistant to
sulfadoxine/
pyrimethamine

Not severe
Severe

Chloroquine (Aralen)PO1
Chloroquine IV3

Not severe

Sulfadoxine/pyrimethamine
PO3

Severe
Not severe
Severe

Not severe
Severe

P. vivax
P. ovale
P. malariae

quinine PO5
quinine IV6

Not
severe
Severe

Mefloquine (Lariam) PO8

quinidine (Quinalam) IV9
quinine IM7

quinine
PO5
tetracycline
quinine IV6
artesunate IV10
artemether IM11
Chloroquine PO,
primaquine 12
Chloroquine PO1

or

quinine PO5
quinine IM7

quinine (Quinamm) IV6

D. Multidrug-resistant

Mixed Infections
Species
Unknown

Sulfadoxine/pyrimethamine (Fansidar)
PO2
Chloroquine IV4

plus

followed

See 5.1 below

quinine IV9
Quinine IM7

by

PO

Mefloquine PO followed by
primaquine PO12
Mefloquine PO8

Treat as if P. falciparum, then threat other

species as indicated13

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