Malaria basics

The main points

The
protozoan
genus
Plasmodium
is
responsible for malaria and has four medically
important species:

Plasmodium falciparum

Plasmodium vivax

Plasmodium Malariae

Plasmodium ovale
The most vicious of these is P. falciparum
because it is rapidly fatal and is responsible
for most malaria related deaths.
Mosquito-transmitted malaria is the greatest
public health problem in large parts of the
world with more than 500 million clinical cases
and over 3 million deaths every year, mostly in
African children under five years.
Every 20 seconds, a child dies of malaria.

 Malaria occurs in most of the tropics of

the
world
with
P.
falciparum
predominating in subSaharan Africa
through to New Guinea.
P. vivax is more common on the Indian
subcontinent, in Mexico & in Central
America
with
the
prevalence
of
falciparum and vivax malarias being
about the same in Asia, Oceania and
South America.
Infrequent P. malariae is found in most
endemic areas, especially subSaharan
Africa that has also 90 % of the deaths.
P. ovale is unusual outside Africa,
although it can be found in southern
India. Also, malaria can be a travelers

By 1970 malaria eradication had

succeeded with DDT in all Europe.

Malaria used to be prevalent in Russia,
USA & Canada.
It was prevalent around the
Mediterranean, Italy, Greece, Yugoslavia,
Bulgaria, Turkey and southern Britain.
It had also been eradicated in Russia,
North America, several middle eastern
countries, large parts of South America,
the Caribbean, Australia, Japan and
Taiwan.

Group 1:
A: Countries which have eliminated malaria: Bahrain, Jordan, Kuwait, Lebanon, Libyan
Jamahiriya, Palestine, Qatar, Tunisia, United Arab Emirates
B: Countries with very limited malaria transmission in residual foci: Egypt, Morocco,
Oman and Syrian Arab Republic
Group 2: Countries with low malaria burden limited to certain areas and with effective
malaria programmes: Islamic Republic of Iran, Iraq and Saudi Arabia
Group 3: Countries with moderate/ high malaria burden, weak health system and/or
complex emergencies: Afghanistan, Djibouti, Pakistan, Somalia, Sudan, Yemen

Malaria has always had a greater impact

on humans than any other parasite or

infectious agent.
Malaria is a rural disease due to the
presence of the female Anopheles
mosquito vector. Can mosquito vector
transmission be lowered? How? In 1956
the World Health Organization (WHO)
began a global malaria eradication
program,
mainly
because
of
the
effectiveness of DTT in killing the
mosquito vectors.
This is an incredibly good pesticide,
cheap
to
make,
long-lasting
and
apparently harmless to humans!

One biological reason for the defeat was

the development of some resistance to

pesticides by the vectors, and another
was the development of some drug
resistance by the parasite itself.
But . . . When health authorities do not
have the money or have the will to spend
it on vector control, they often lie and
promote underestimates of the threat.
Transgenic mosquitoes incompetent to
transmit the sporozoites are a bright
shiny hope.

How is global malaria to be managed?

Who pays the bill? Political will,

public health education and similar
social factors sometimes centering on
poverty shape the WHO campaign for
eradication.
Global eradication as an ideal may be
impossible for fault of gigantic
financing, yet the eradication of
malaria is long overdue in countries,
not willing to spend the money.
Many populations across the world
have no idea of the health threats
that they live under.

In India 75 million cases in 1950 were down to

100,000 cases by 1970. Transmission rates in

Africa and India were severely reduced. Malaria
had been almost eliminated in Sri-Lanka. All of
this progress was lost because of DDT hysteria.
The
enormous penalty for hysteria and
mendacity includes losing control of filariasis.
Still, the WHO did know what would happen if
DDT was suspended.
Mendacity is exhibited by crying about drug
resistance, while not honestly discussing or
otherwise even mentioning lifesaving DDT.
Affluent countries without malaria decided to
ban DDT whose main features are low cost and
efficient residual effect.

The vector life cycle

All four species are transmitted through:
The

bite of an infected female Anopheles species

mosquito.
Malaria also can be transmitted via a blood transfusion
or congenitally between mother and fetus.

Malaria-carrying Anopheles mosquitoes tend to bite

only near dusk and dawn. The vector, the Anopheles
species mosquito, passes plasmodia, which are
contained in its saliva, into its host while obtaining a
blood meal. Plasmodia enter circulating RBCs and
feed on the hemoglobin, other proteins and glucose
within
the
cells.

Insect life cycles are well known: eggs, pupas, larvas and adults.

Anopheles mosquitoes feeding on infected hosts ingest sexual

forms developing in RBCs. The female macrogametocytes and
male microgametocytes mature in the mosquitos stomach and
combine forming a zygote.
Over 5-10 hours, the zygote in the mosquito differentiates into a
cigar-shaped invasive ookinete. During the differentiation of the
ookinete the diploid set of chromosomes divides as the first step
in a two stage meiosis, the second stage takes place at the start
of sporogony.
The ookinetes force themselves between the epithelial cells to
the outer surface of the mosquito stomach, and form into small
spheres called oocysts.
The oocysts enlarge as the nucleus divides, eventually rupturing
and releasing thousands of motile sporozoites into the body
cavity.
The sporozoites migrate to the salivary glands, making the
female mosquito infective. The vector phase of the life cycle,
called sporogony, is complete in 8 to 35 days depending on
species and environmental conditions.

Development time from egg to adult mosquito depends on species

and temperature, ranging from 7 days at an average temperature

of 31C, to 20 days at an average temperature of 20C. Average
life span of a female mosquito under favorable conditions is about
2 weeks with some living 3-4 weeks.
Females lay eggs 3-6 days after they emerge. Single blackish
anopheline eggs of about 0.5 mm length air-filled floats that let
them drift on the water surface. Eggs hatch 2-3 days after being
laid. The larvas do not have the air tube or siphon found in other
mosquito larvas. They float horizontally on the surface of the
water, and after molting three times develop into pupas that
emerge as adults after 2-4 days. Needing a blood meal for the
development of their eggs, all female mosquitoes bite at less than
3 km from their breeding sites, but many live within just 30 m
diameter from where they were born. Also note that anophelene
mosqitoes are dusk and dawn biters like Aedes aegypti.
How long does sporogony take in what conditions and in what
vector hosts? How do such variables affect VECTOR
COMPETENCE ?

The mammalian life cycle

Plasmodia replicate inside the RBC. This
replication induces RBC cytolysis and
causes the release of toxic metabolic
byproducts into the bloodstream.
These symptoms include chills, headache,
myalgia and malaise, occurring in cycles.
The parasite also may cause splenomegaly,
jaundice and anemia. The symptoms relate
to blood cell destruction.
P. falciparum may induce kidney failure,
coma and death.

Merozoite is the traditional term for

vegetative
or nonsexual state =
trophozoite = schizont.
A
hepatic schizont contains many
thousands of tiny, invasive merozoites,
created in a single segmentation. These
asexual merozoites are the smallest and
shortest lived form of the life cycle.
Within a few minutes, they invade RBCs.
The apical complex of the merozite is
specialized to recognise and attach to
epitopes on the RBCs

All

infected liver cells parasitized with P.

falciparum and P. malariae rupture and release
merozoites at about the same time.
In contrast, P. vivax and P. ovale have two
exoerythrocytic forms. The primary type
develops, causes liver cell rupture, and releases
merozoites just as in P. falciparum and P.
malariae. The other form, which develops
concurrently, is known as the hypnozoite.
Sporozoites that enter liver cells differentiate
into
nonsexual
hypnozoites
that
remain
dormant for weeks, or even years. The
hypnozoites
activate
and
undergo
exoerythrocytic schizogony, forming a wave of
merozoites that cause a relapse.

Relapses impede eradication attempts

by causing unexpected local outbreaks.

Of course, the vector must live long
enough for sporogony to be completed if
it is to become infective.
Why are sporozoites so very important?
Because they invade both mosquito
salivary glands and human hepatocytes.
Their invasiveness then makes them a
target antigen.

Clinical symptoms
Include the following:
cough, fatigue, malaise, arthralgia, myalgia,
and paroxysm of shaking chills and sweats.
The classic paroxysm begins with a period of
shivering and chills, which lasts for 1-2 hours
followed
by
high
fever.
Paroxyms of varying 48 hours belong to vivax,

ovale and falciparum malaria, whereas 72

hours belongs
to malariae infections.

Clinical Symptoms
Malaria is characterized by severe undulating fever

(paroxyms) occurring every 48 or 72 hours,

depending on the species, varying from 48 hours in
P.vivax, P. ovale, and P. falciparum malaria, to 72
hours in P. malariae infections.
The 48 hour fever is called tertian because it occurs
every third day: fever on day 1, no fever on day 2,
fever on day 3 and so on.
The 72 hour fever is called quartan, because it
returns on every fourth day.
The erythrocytic schizogony cycle (vegetative)
becomes synchronized, and the febrile paroxysms
become consistent.

Clinical Features of Malaria

P. vivax,

P. falciparum

P.

Malariae
P. ovale
Incubation
Type of fever
Quartan

8-24 d
Tertian

8-24 d

15-30 days

Aperiodic
quotidian
Tertian

Exoerythrocytic
cycle
Yes

No

No

Uncomplicated malaria
Fever and any of the
following:
Headache,
Body and joint pains
Feeling cold and sometimes

shivering
Loss of appetite and sometimes
abdominal pains
Diarrhoea, nausea and vomiting
Splenomegaly

Differential diagnosis for

uncomplicated malaria
Consider other illnesses, such as:
Upper respiratory tract infection
(Pharyngitis, tonsillitis, ear infection)
pneumonia
measles
dengue
influenza
typhoid fever
Remember that the patient may be

suffering from more than one illness.

SEVERE MALARIA
Severe or complicated malaria definition:

Fever and any of the following:

Impaired consciousness

Anxiety, palpitation and sweating

Convulsions or fits with this fever

Fast or difficult breathing

Vomiting every feed / unable to feed

Pale hands, tongue and inner parts of the eyelid

Generalized body weakness

Dehydration

Jaundice

Severe malnutrition

Dark urine or no urine

As many as 30% of nonimmune adults infected

with P falciparum suffer acute renal failure, some

with seizures. Blackwater fever is hemoglobinuria
with the passage of dark-colored urine
Noncardiogenic pulmonary edema is most common
in pregnant women and results in death in 80% of
patients.
Profound hypoglycemia often occurs in young
children and pregnant women.
The most prominent symptoms all relate to loss of
RBCs:
a) tachycardia
b) anemia
c) fever
d) hypotension
e) splenomegaly

The principal signs of cerebral malaria

are
seizures
and
unconsciousness,
usually preceded by a severe headache.
Neurologic examination may include
contracted or unequal pupils, a Babinski
sign, and absent or exaggerated deep
tendon reflexes. Cerebrospinal fluid
examination shows increased pressure,
increased protein, and minimal or no
pleocytosis. High fever, 41 to 42C with
hot, dry skin may occur.

These symptoms of cerebral malaria are caused by

microvascular obstruction that prevents the exchange

of glucose and oxygen at the capillary level,
hypoglycemia, lactic acidosis, and high-grade fever.
These events impair brain function, yet rapid and full
recovery most often follows prompt treatment.
Renal failure, due to acute tubular necrosis, is a
common complication of severe P. falciparum
infections in nonimmune persons. The renal tubules
can become clogged with hemoglobin and malarial
pigment released during massive hemolysis, and
microvascular obstruction can cause anoxia and
glucose deprivation.
An enlarged, tender spleen and a palpable liver was
often present by the second week of infection.

 Often fatal, acute pulmonary edema can develop

rapidly
and
is
associated
with
excessive
intravenous
fluid
therapy.
Fast,
labored
respiration, with shortness of breath, a nonproductive cough, and physical findings of moist
rales and rhonchi are usually present. Chest X-rays
usually show increased bronchovascular markings.
Most patients with falciparum malaria complain of
loss of appetite and nausea. However, in some
patients (especially young children), additional
symptoms including vomiting, abdominal pain,
watery diarrhea, and jaundice.
Anemia is due to RBC destruction of all ages upon
merozoite release as often seen in falciparum
infections. P. vivax and P. ovale require young red
blood cells (reticulocytes) and P. malariae requires
mature blood cells for infection.

Differential diagnosis for

complicated malaria
Consider other illnesses such as:
Measles
Meningitis
Tonsillitis
Dengue
Otitis media
Influenza
Pneumonia
Typhoid fever
Tuberculosis
Hypoglycemia

Laboratory identifications with

Giemsa
The heart of an eradication campaign is

the thick blood film. Interest focuses on

good Geimsa staining. You must be able
to identify the gametocytes of the 4
species, but first find out if malaria
parasites are present.
Examine a thick Giemsa slide, especially
if from a field survey. The hospital slide
from a patient already diagnosed needs
to be identified to the species level.

Diagnosis

by the polymerase chain

reaction (PCR) can become routine in
some laboratories, whereas in most the
cost is prohibitive.
Dipsticks
for
histidine-rich
protein
(HRP2) of P. falciparum are accurate, fast
and cheap. Other simple immunological
highlights may develop. Present rapid
dipstick methods stand out.

Anti Malarial Drugs

Chloroquine is a 4-aminoquinoline.
Amodiaquine is a Mannich base 4-aminoquinoline.
Sulfadoxine is a slowly eliminated sulfonamide.
Pyrimethamine is a diaminopyrimidine used in combination

with a sulfonamide, usually sulfadoxine (Fansedar) or

dapsone.
Mefloquine is a 4-methanolquinoline and is related to
quinine.
Artemisinin and its derivatives
Artemisinin, also known as qinghaosu
Artemether is the methyl ether of dihydroartemisinin.
Artesunate is the sodium salt of the hemisuccinate ester of

artemisinin.
Dihydroartemisinin is the main active metabolite of the
artemisinin derivatives
Artemotil, previously known as arteether, is the ethyl ether of
artemisinin

Anti Malarial Drugs

Lumefantrine belongs to the aryl aminoalcohol group of

antimalarials, which also includes quinine, mefloquine

and halofantrine.
Primaquine is an 8-aminoquinoline and is effective
against intrahepatic forms of all types of malaria
parasite.
Atovaquone is a hydroxynaphthoquinone
Proguanil is a biguanide compound.
Chlorproguanil is a biguanide and is given as the
hydrochloride salt.
Dapsone is a sulfone.
Quinine is an alkaloid derived from the bark of the
Cinchona tree.
tetracyclines are a group of antibiotics
Doxycycline is a tetracycline derivative
Clindamycin is a lincosamide antibiotic

Treatment of Malaria
1) P. vivax, P. ovale:
Oral chloroquine 10 mg/kg (max. 600 mg) followed by 5
mg/kg (max. 300 mg) after 6, 24 and 48 hours
Oral primaquine 15 mg/kg / day x 14 days to prevent relapse.

2) P. falciparum:
Chloroquine sensitive : As above.
Chloroquine resistant :
Pyrimethamine 25 mg + sulphadoxine 500 mg tablets - 3 tablets
single dose for adults
OR - Quinine sulphate 650 mg (10 mg/kg) salt orally TDS times 7
days, plus Tetracycline 250 mg QDS times 7 days

Multidrug resistant :
Mefloquine 15-25 mg/kg (max 1.5 g) single dose orally
OR - Artesunate 200 mg on first day followed by 100 mg daily times
4 days.

Severe falciparum malaria (including cerebral malaria):

Quinine IV 10 mg/kg over 4 - 8 hours TDS times 7 days (oral
therapy when possible)
Quinine resistant cases :

Artesunate 2 mg/kg IM followed by 10 mg/kg after 6 hours on first

day, then daily times 4 days
OR - Artemether 160 mg (3.2 mg/kg IM) on first day; 80 mg (1.6
mg/kg IM) on days 2 - 5

Supportive Therapy : IV fluids, blood transfusion, etc.

Chemoprophylaxis:
Usually chloroquine 300 mg base once weekly, starting 1

week before exposure.

Alternatives:

Mefloquine,
exposure.
Doxycycline,
Chloroquine,
exposure +
exposure

250 mg base weekly, starting 1 week before

100 mg daily, starting 2 days before exposure
300 mg base weekly, starting 1 week before
proguanil 200 mg daily, starting 2 days before

Antimalarial combination therapy

Antimalarial combination therapy is the

simultaneous use of two or more blood

schizontocidal drugs with independent modes
of action and thus unrelated biochemical
targets in the parasite.
The concept is based on the potential of two
or more simultaneously administered
schizontocidal drugs with independent modes
of action to improve therapeutic efficacy and
also to delay the development of resistance to
the individual components of the combination.

The rationale for combining antimalarials with

different modes of action is twofold:

(1) the combination is often more effective.
(2) in the rare event that a mutant parasite that is
resistant to one of the drugs arises de novo during
the course of the infection, the parasite will be killed
by the other drug.

This mutual protection is thought to prevent or

delay the emergence of resistance.

To realize the two advantages, the partner drugs
in a combination must be independently effective.
The possible disadvantages of combination
treatments are the potential for increased risk of
adverse effects and the increased cost.

Artemisinin-based combination therapy (ACT)

Artemisinin and its derivatives (artesunate, artemether, artemotil,

dihydroartemisinin) produce rapid clearance of parasitaemia and

rapid resolution of symptoms. They reduce parasite numbers by a
factor of approximately 10 000 in each asexual cycle, which is
more than other current antimalarials (which reduce parasite
numbers 100- to 1000-fold per cycle).
Artemisinin and its derivatives are eliminated rapidly. When
given in combination with rapidly eliminated compounds
(tetracyclines, clindamycin), a 7-day course of treatment with an
artemisinin compound is required.
but when given in combination with slowly eliminated
antimalarials, shorter courses of treatment (3 days) are effective.
The evidence of their superiority in comparison to monotherapies
has been clearly documented.

ACTs for uncomplicated falciparum

malaria
The following ACTs are recommended:
artemether-lumefantrine
artesunate - amodiaquine
artesunate + mefloquine
artesunate + sulfadoxine-pyrimethamine
dihydroartemisinin piperaquine*

efficacy of ACTs depend on the efficacy of the partner medicine

The artemisinin derivatives (oral formulations) and partner medicines of

ACTs should not be used as monotherapy in the treatment of
uncomplicated malaria

Defective globin genes.

About

250 million people, 4.5 % of the world

population, are carriers of a defective globulin gene.
Each year about 300,000 homozygotes are born
about equally divided between sickle cell disorders
and thalassemia syndromes.
Malarial parasites feed on RBCs. Then clinical
symptoms like plain anemia and just about
everything else are strongly affected by RBC
destruction. Are there mutant hemoglobin molecules
unsuitable to mosquitoes? Yes. One causes sickle cell
anemia, and others cause - and -thalassemias.
This causes abnormal RBCs that again confer
resistance to malaria.

Another associated genetic blood

disease is glucose-6-phosphate
dehydrogenase deficiency in RBCs. Only
men are affected as this is an Xchromosome linked trait. Glucose-6phosphate dehydrogenase is involved in
protecting RBCs from damage by free
radicals and in particular reactive oxygen
intermediates.

The establishment of the Global Fund to

Fight AIDS, Tuberculosis and Malaria

(GFATM) is providing significant new
grants to help countries accelerate
implementation of their plans to roll
back malaria.