‫‪Malaria‬‬

‫‪Dr. Talal Saeed Alwajeeh‬‬

‫المحاضرة الحادية عشر والثانية عشر‬

 Malaria
► Malaria is one of the most common infectious diseases in the world.
► Malaria remains the third leading cause of death attributable to an infectious
disease worldwide, with an estimated 2.7 million deaths per year , one million of
them are children according to WHO records.
► Malaria is a mosquito-borne disease caused by small, one-celled parasites called
Plasmodium that infect and destroy red blood cells.
► The genus Plasmodium belongs to the phylum Apicomplexa and consists of
nearly 200 species that infect humans.
► Five different Plasmodium can cause disease in humans (Causative agents of
human malaria)
1. Plasmodium falciparum
2. Plasmodium vivax
3. Plasmodium ovale
4. Plasmodium malariae
5. Plasmodium knowlesi
► Plasmodium falciparum is the most prevalent and the most dangerous,
responsible for over 90% of deaths due to malaria.
Distribution
■ P. falciparum are found in the tropics and subtropics areas . It is well known to be
the fatal form of human malaria and is also known as malignant tertian.
■ P. vivax is found in the tropics, subtropics, and some temperate regions; it is the
most prevalent malaria species.
■ P. ovale is found in West Africa.
■ P. malariae occurs in subtropical and temperate areas.
■ P. knowlesi is found in southeastern Asia , a monkey malaria is distributed in
Southeast Asia where the reservoir macaques are prevalent.
■ P. vivax and P. falciparum account for more than 95% of infections.
Epidemiology
❖ Malaria occurs in many tropical and sub-tropical areas of the world, particularly
sub-Saharan Africa, South east Asia, the Middle East, and Central and South
America.

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❖ About 106 countries in the world are at risk of transmission of malaria infection.
❖ It causes significant morbidity and mortality especially in regions with limited
resources.

Malaria in Yemen
❖ Malaria still one of the major public heath problem in the republic of Yemen.
❖ The predominant species is Plasmodium falciparum with only minimal cases
caused by Plasmodium vivax.

Habitat
□ In human , the parasites are found in the erythrocytes and hepatocytes.

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Vectors & Transmission
► Human malaria is transmitted by over 60 species of female Anopheles mosquito.
► Malaria is transmitted to people through the bites of infected female Anopheles
mosquito during the feeding on blood of a vertebrate host.

Morphology
1. Morphology of Plasmodium falciparum
● This is the most pathogenic of all the plasmodium species and responsible for
almost all deaths caused by malaria.
● They infect both young and old erythrocytes.
● The infected erythrocytes are not enlarged.
● The early ring form is fine, measuring 1/6 the size of red blood cell (RBC).
● Rings are often seen attached along the margin of the red cell (Appliqué or accolé
forms) and Double chromatins are common.
● Multiple rings may be seen within a single erythrocyte.
● Late trophozoites and schizonts are not usually seen in the peripheral blood.
● The mature schizont has 8–24 (usually 16) merozoites.
● A good staining will show coarse dots which are called Maurer’s clefts.
● The mature gametocytes are crescent or banana shaped.

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 (A) (B)
Thin blood smear showing different forms of Plasmodium falciparum :
(A) Ring form
(B) Gametocyte

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2. Morphology of Plasmodium vivax
● Merozoites of P. vivax prefer reticulocytes.
● All erythrocytic stages can be seen in peripheral smears.
● The infected erythrocytes are enlarged and with good staining will show numerous
fine granules known as Schuffner’s dots in the cytoplasm of the RBC.
● The ring is about 1/3 the size of RBC.
● Ring form develops rapidly into trophozoite which is amoeboid shape.
● There are about 12–24 (usually 18) merozoites per schizont.
● Both male (pale blue cytoplasm) and female (dark blue cytoplasm) gametocytes
are round or oval, large, filling almost the enlarged RBC.

Thin blood smear showing different forms of Plasmodium vivax :

(A) Ring form
(B) Gametocyte
(C) Schizont

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3. Morphology of Plasmodium ovale
● It is the rarest of all plasmodium infecting humans.

● The infected erythrocytes are normal or slightly enlarged and may be fimbriated.

● Schuffner’s dots are present in the cytoplasm of the infected RBC and are seen

under good staining.

● The trophozoites resemble those in P. vivax, but are usually more compact, with a

large chromatin dot and less amoeboid appearance.

● Schizonts are round to oval containing 6-14 (usually 12) merozoites (with large

nuclei) clustered around mass of dark-brown pigment.

● Both male and female gametocytes are round to oval , compact and may fill the

RBC.

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4. Morphology of Plasmodium malariae
• Plasmodium malariae prefers older erythrocytes.
• Ring form with thick cytoplasm and a large chromatin dot. “Bird's-eye” forms
may appear.
• Infected erythrocytes may be normal size or slightly smaller.
• Ttrophozoites stretch across the diameter of the erythrocyte and seen as a band
form and/or “basket” form.
• Infected RBCs rarely contain Ziemann’s stippling (fine dots).
• Mature schizont filling the RBC and containing 6-12 (usually 8) merozoites,
which usually present as a rosette appearance.
• Both male and female gametocytes occupy nearly the entire RBC.

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Life cycle
• Malaria parasite completes its life cycle in two hosts:
1. Female Anopheles mosquito is the definitive host where the sexual cycle
(sporogony) takes place.
2. Man acts as intermediate host where the asexual cycle (schizogony) takes place.
Asexual cycle (in intermediate host)
• The asexual multiplication is known as schizogony.

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• Because this asexual cycle occurs in man, it is also called the vertebrate, intrinsic,
or endogenous phase.
• In humans, schizogony occurs in two locations - (1) in the red blood cell
(erythrocytic schizogony) and (2) in the liver cells (exoerythrocytic schizogony or
pre erythrocytic schizogony).
• The products of schizogony, whether erythrocytic or exoerythrocytic, are called
merozoites.
Sexual cycle (in definitive host)
• Female Anopheles mosquito represents definitive host, in which sexual forms takes
place. Although the sexual forms of the parasite (gametocytes) originate in human
RBCs.
• Maturation and fertilization take place in the mosquito, giving rise to a large
number of sporozoites. Hence, this phase of sexual multiplication is called
sporogony. It is also called the invertebrate, extrinsic, or exogenous phase.
Human cycle (schizogony)
• Humans acquire infection from the bites of infective female Anopheles mosquito.
• The sporozoites, which are the infective forms of the parasite, are present in the
salivary gland of the mosquito.
• They are injected into blood capillaries when the mosquito takes a blood meal.
• The sporozoites circulate in the blood stream and enter the liver cells
(hepatocytes).
Exoerythrocytic cycle
• Within 30 min, the sporozoites reach the liver and enter the hepatocytes to initiate
the stage of pre erythrocytic schizogony.
• In P. vivax and P. ovale, they form schizonts which persist and remain dormant
(hypnozoite).
• From time to time, the dormant schizonts are reactivated and release merozoites,
which go on to infect RBCs causing clinical relapse.
Erythrocytic cycle
• The merozoites released by pre-erythrocytic schizonts in the liver invade the
RBCs and form rings or young trophozoites.

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• The parasite feeds on the haemoglobin. It does not metabolize haemoglobin
completely and therefore, leaves behind a hematin-globin pigment called the
malaria pigment or hemozoin pigment, as residue.
• As the ring form develops, it enlarges in size becoming irregular in shape and
shows amoeboid motility. This is called the amoeboid form or late trophozoite
form.
• Its nucleus starts dividing by mitosis followed by a division of cytoplasm to
become mature schizonts (8-32 merozoites).
Gametogony
• After a few erythrocytic cycles, some of the merozoites that infect RBCs do not
proceed to become trophozoites or schizonts but instead, develop into sexually
differentiated forms, the gametocytes.
• They grow in size till they almost fill the RBC, but the nucleus remains undivided.
• Development of gametocytes generally takes place within the internal organs and
only the mature forms appear in circulation.
• The mature gametocytes are round in shape, except in P. falciparum, in which
they are crescent-shaped.
• In all species, the female gametocyte is larger (macrogametocyte) and smaller
male gametocyte (microgametocyte).
Mosquito Cycle (Sporogony)
• When a female Anopheles mosquito ingests parasitized erythrocytes along with
its blood meal, the asexual forms of malaria parasite are digested.
• The gametocytes undergo further development in the midgut (stomach) of
mosquito.
• The nuclear material and cytoplasm of the male gametocytes divide to produce 8
microgametes (exflagellating male gametocytes).
• The female gametocyte (macrogamete) is fertilized by the microgamete to form
zygote.
• The zygote develops into a motile form called ookinete.
• Ookinete penetrates the epithelial lining of the mosquito stomach wall and comes
to lie beneath the basement membrane.
• It forms an oocyst within which numerous sporozoites are formed.
• The mature oocyst ruptures releasing sporozoites into the body cavity, from where
some find their way to the salivary glands.

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• The mosquito is now infective and when it feeds on humans, the sporozoites are
injected into skin capillaries to initiate infection.
• The time taken for completion of sporogony in the mosquito is about 1–4 weeks,
depending on the species and environmental temperature.

Incubation period
• It is the interval between the infective mosquito bite and the first appearance of
clinical symptoms.
• The average incubation periods of different species of Plasmodium are as follows:
P. falciparum 12 (8–14) days
P. vivax 14 (8–31) days
P. ovale 14 (8–31) days
P. malariae 28 (18–40) days

Pathogenesis and Clinical Features

• The pathogenesis of P. falciparum human infection is a complex.

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• There are two features playing a role in the pathogenesis and severity of
falciparum malaria:
1. The ability to invade erythrocytes of all ages causing very high parasitemia.
2. The capacity to cytoadhere to the vascular endothelium of blood vessels of
internal organs (lung, heart, brain, liver, and kidney).
• The greater virulence of P. falciparum compared to other human malaria
parasites is the ability of parasites to infect RBCs stages of different ages.
• Plasmodium falciparum and Plasmodium vivax are the main causes of disease
and death from malaria.
Cytoadherence:
• It refers to binding of infected erythrocytes to endothelial cells.
• It is mediated by a specialized antigen called as P. falciparum erythrocyte
membrane protein-1(PfEMP-1).
Rosetting:
• It refers binding of infected erythrocytes to uninfected erythrocytes.
• PfEMP1 also plays an important role in rosetting, as it can adhere to complement
receptor 1 (CR1) and blood group A antigen present on the uninfected
erythrocytes.
• The clinical symptoms of malaria are primarily due to schizont rupture and
destruction of erythrocytes.
• The typical picture of malaria consists of fever, anemia and splenomegaly.
• Severe headache, nausea, and vomiting are common.
• The febrile paroxysm comprises of 3 stages: cold stage, hot stage, and sweating
stage.
• In the cold stage, that lasts for 15–60 minutes, the patient experiences intense cold
and uncontrollable shivering.
• This is followed by the hot stage, lasting for 2–6 hours, when the patient feels
intensely hot. The temperature mounts to 41°C or higher.
• Afterwards comes the sweating stage, when the patient is drenched in profuse
sweat. The temperature drops rapidly and the patient usually falls into deep sleep,
to wake up refreshed.
Complications of falciparum malaria
►Cerebral Malaria ► Septicemic Malaria
►Blackwater fever ► Acute renal failure

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►Hypoglycemia (<40 mg/dL) ►Severe anemia (Hb <5 g/dL)
►Severe jaundice

Fig. Major pathological changes in organs in malaria

Cerebral malaria:
• Occurs due to plugging of brain capillaries by the rosettes of sequestered
parasitized RBCs leading to vascular occlusion and cerebral anoxia.
• Cerebral malaria manifests as diffuse symmetric encephalopathy characterized by
generalized convulsion in 10% of adults and up to 50% of children.
Pernicious (malignant) malaria:
• It is characterized by blackwater fever, algid malaria and septicemic malaria.
Black water fever:
• This syndrome is characterized by sudden intravascular hemolysis followed by
fever, hemoglobinuria and dark urine.
• It occurs following quinine treatment to subjects previously infected with P.
falciparum.

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Algid malaria:
• This syndrome is characterized by peripheral circulatory failure, rapid thready
pulse with low blood pressure and cold clammy skin.
• There may be severe abdominal pain, vomiting, diarrhea and profound shock.
Septicemic malaria:
• It is characterized by high continuous fever with dissemination of the parasite to
various organs, leading to multiorgan failure.
• Death occurs in 80% of the cases.
Severe jaundice:
• More common among adults than children; it results from hemolysis, hepatocyte
injury and cholestasis.
Severe normocytic , normochromic anemia:
• Characterized by hematocrit of less than 15% or hemoglobin level of less than 5
g/dL with parasitemia level of more than 100,000/μL.
Renal failure:
• It occurs due to erythrocyte sequestration in renal microvasculature leading to
acute tubular necrosis.
• In 10% of cases renal dysfunction progressing to acute renal failure may occur.
• It is common among adults than children.
Hypoglycemia:
• Hypoglycemia is common in patients following quinine therapy or with
hyperparasitemia.
Quartan malarial nephropathy
• It is a chronic complication seen with P. malariae.
• It occurs due to injury to the renal glomeruli by the immune complexes, resulting
in nephrotic syndrome.

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Differences between recrudescence and relapse

Recrudescence Relapse

Seen in P. falciparum and P. malariae Seen in P. vivax and P. avale

Due to persistence of the parasite at a Due to reactivation of hypnozoites

subclinical level in circulation present in liver cells

Occurs within a few weeks or months of Occurs usually 24 weeks to 5 years after
a previous attack the primary attack

Can be prevented by adequate drug Can be prevented by giving primaquine

therapy or use of newer antimalarial to eradicate hypnozoites
drugs in case of drug resistance

Laboratory Diagnosis
❖ Clinical diagnosis is based on the patients' signs and symptoms, and on physical
findings at examination.
❖ Laboratory diagnosis include:
1. Microscopic examination (Gold standard) of blood films stained with giemsa
stain.
Thick and thin blood smears are the methods of choice for diagnosing infections
with a Plasmodium species.
Thick smear are used for detecting the presence of parasites, and the thin smears are
used for determining and identification of species.

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2. Rapid diagnostic tests (RDTs)
• The tests are based on the detection of malaria parasite antigens in human blood,
using immunochromatographic methods.

3. Serological methods
• The tests are based on the detection of malaria parasite antibody using
immunofluorescence antibody testing (IFA) and ELISA.
4. Molecular tools
• Are more sensitive for detecting low level of infections by PCR on blood sample.

Treatment
Uncomplicated Benign Malaria
• Positive P. vivax, P. ovate and P malariae cases are treated with Chloroquine 25
mg/kg divided over 3 days.
• For prevention of relapse rate of vivax malaria, Primaquine is given in a dose of
0.25 mg/ kg daily for 14 days under supervision..
• In case of chloroquine resistance: Quinine is given in a dose of 600 mg 8 hourly
for 7 days along with doxycycline 100 mg/ day or tetracycline.
Complicated Falciparum Malaria
Treatment of falciparum malaria is based on area resistant or sensitive to
chloroquine.

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• Artemisinin combination therapy (ACT) is recommended in chloroquine
resistant areas where as chloroquine can be given in sensitive areas.
• ACT consists of a combination of artemisinin derivative (Artemisinin or
artemether or arte-ether) and a long acting antimalarial drugs like sulfadoxine-
pyrimethamine, mefloquine or lumefantrine.
• Fansidar (sulfadoxine 500 mg and pyrimethamine 25 mg) 3 tablets of fansidar in
a single oral dose.
• In pregnancy, quinine is recommended in first trimester whereas ACT is given in
second and third trimester.
• Treatment of unconfirmed cases or mixed infection with P. falciparum should
be treated as falciparum malaria plus primaquine is given for radical cure.

Prevention and Control

1. Chemoprophylaxis
• Chemoprophylaxis is recommended for travelers going to endemic areas. Its
provide effective protection.
• Drugs that are used for chemoprophylaxis of malaria include : Chloroquine 300
mg or proguanil 400 mg, or mefloquine 250 mg weekly or doxycycline 100 mg
daily.
• Prophylaxis should begin 1 week before travelling and be continued while in the
endemic area and for 4–6 weeks after departure from endemic area.
2. Vector Control Strategies
• Insecticide residual spraying (IRS): The spraying of the indoor surfaces of house
with residual insecticides.
• Insecticide treated bed nets (ITN)
• Use of repellants, protective clothing, mosquito coils and screening of house.
3. Anti-larval Measures
• Larvicide: Use of mineral oil or Paris green has been extensively used to kill
mosquito larvae and pupae.

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