MALARIA

Dr.T.V.Rao, MD
 Ancient History of Malaria
Malaria parasites have been with us since
the dawn of time. They probably originated
in Africa (along with mankind), and fossils
of mosquitoes up to 30 million years old,
show that the malaria vector, the malaria
mosquito, was present well before the
earliest history.
Malaria and Man
 Hippocrates and Malaria
Hippocrates, a physician
born in ancient Greece,
today regarded as the
"Father of Medicine", was
the first to describe the
manifestations of the
disease, and relate them
to the time of year and to
where the patients lived.
 Malaria

Name is derived from Italian

Mal’ aria or bad air
Malaria continues to be most important
cause of fever and morbidity in the
Tropical world
Malaria has been eradicated from Europe,
Most of North America, USA South
America Korea and Japan,
History – Events on Malaria
1880 - Charles Louis Alphose Lavern
discovered malarial parasite in wet mount
1883 - Methylene blue stain - Marchafava
1891 - Polychrome stain- Romanowsky
1898 - Roland Ross - Life cycle of parasite
transmission, wins Nobel Prize in 1902
1948 - Site of Exoerythrocytic development in
Liver by Shortt and Garnham
 Major Developments in 20th
Century
1955 - WHO starts world wide malaria
eradication programme using DDT
1970 – Mosquitos develop resistance to
DDT Programme fails
1976 – Trager and Jensen in vitro
cultivation of parasite
 Lavern and Ronald Ross
Pioneered the Events on Malaria
Nature of parasite as Drawn by
Lavern
 Nobel Prizes in Malaria
The discovery of this
parasite in mosquitoes
earned the British
scientist Ronald Ross the
Nobel Prize in Physiology
or Medicine in 1902. In
1907, Alphonse Lavern
received the Nobel prize
for his findings that the
parasite was present in
human blood.
 Introduction
Malaria is probably one of the oldest diseases known to
mankind that has had profound impact on our history.

It is a huge social, economical and health problem,

particularly in the tropical countries.

Malaria is a vector-borne infectious disease caused by

single-celled protozoan parasites of the genus
Plasmodium.

Malaria is transmitted from person to person by the bite

of female mosquitoes.
Female Anopheles Mosquitos
transmit Malaria
Global problem
 What causes Malaria
Malaria is caused by a parasite called
Plasmodium, which is transmitted via the
bites of infected mosquitoes. In the human
body, the parasites multiply in the liver,
and then infect red blood cells.
Transmission of Malaria do not occur
<160c and >330c
Do not occur > 2000 meters altitude.
Parasites Cause of Malaria
Malaria is caused by an infection by one of
four single celled Plasmodia species, they
are: falciparum, vivax, malariae, and
ovale. The most dangerous of the four
is.P.falciparum
Falciparum most Dangerous
Falciparum accounts for 90% of deaths
due to malaria and vivax is the most
widely spread species because it exists in
both temperate and tropical climates
(Encarta). The malaria life cycle is a
complex system with both sexual and
asexual aspects .
Why it is important in Medicine
Malaria remains the world's most
devastating human parasitic infection.
Malaria affects over 40% of the world's
population. WHO, estimates that there
are 350 - 500 million cases of malaria
worldwide, of which 270 - 400 million
are Falciparum malaria, the most
severe form of the disease.
Malaria Kills more people than
AIDS
Malaria kills in one year what AIDS kills
in 15 years. For every death due to
HIV/AIDS there are about 50 deaths due
to malaria. To add to the problem is the
increasing drug resistance to the
established drug.
 Etiology of Malaria
Four Species known to infect Man
1 Plasmodium vivax – Benign Tertian,
Tertian Malaria
2 P.ovale - Ovale tertian Malaria
3 P.malariae – Quartan malaria
4 P.falciparum – Falciparum malaria or
Malignant Tertian malaria.
Structure of Malarial parasite
Events in Humans start with Bite
of Mosquito
Man – Intermediate host.
Mosquito – Definitive host
– Sporozoites are infective
forms
Present in the salivary
gland of female
anopheles mosquito
After bite of infected
mosquito sporozoites are
introduced into blood
circulation.
 Human cycle

1 Pre erythrocytic
schizogony
2 Erythrocytic
Schizogony
3 Gametogony
4 Exoerythrocytic
schizogony
 Pre erythrocytic cycle
Sprozoites undergo developemtnal phase in the
liver cell
Sprozoites are elongated and spindle shaped
become rounded inside the liver parenchyma
Multiple nuclear divisions develop to Schozonts
A Schizont contains 20,000 – 50,000
merozoites.
Life Cycle of Malaria
Period of Pre erythrocytic cycle

1 P.vivax 8 days
2 P.falciparum – 6 days
3 P.malariae - 13 – 16 days,
4 P.ovale 9 days
On maturation Liver cells ruputure
Liberate Merozoites into blood stream
 Affinity of Parasite to
Erythrocytes
P.vivax
P.malariae Infectes only young or
P.ovale Old Erythocytes

P.falciparum Infects all age groups

Also adhere to the endothelial lining of
Blood vessesl
Causes the obstruction, Thrombosis and
Local Ischemias
 Erythrocytic Schizogony
Liberated Merozoites
penetrate RBC
Three stages occur
1 Trophozoites
2 Schizont
3 Merozoite
 Erythrocytic cycle
Ruptured red cells
release Merozoites which
attack new red cells
Continue with Schizogony
Repeated cycles will
continue
In P.falciparum - infected
erythrocytes with
Schizonts aggregate in
the capillaries of brain
and other internal organs
Only ring forms are seen
in the blood smears
 Trophozoites
After invasion grow
and feed on
hemoglobin
Blue cytoplasm and
red nucleus, Called
as Signet ring
appearance
Hence called ring
form
 Schizont

When the Trophozoite is fully developed

becomes compact.
Malarial pigments are scattered through
the cytoplasm
The Nucleus is large and lies at the
periphery starts dividing.
Becomes Schizont
Exo Erythrocytic Schizogony
Some Sprozoites do not undergo
sporogony in the first instance
But go into resting stage called as
Hypnozoites,( hibernation )
Within 2 years reactivate to form
Schizonts release Merozoites and attack
red cell and produce relapses
Absent in P falciparum
 Gametogony
Merozoites differentiate into Male and female
gametocytes
Macrogametocytes also called female
gametocytes
Microgametocyte also called as male
gametocytes
They develop in the red cells
Found in the peripheral blood smears
Microgametocyte of all species are similar in
size
Macro gametocytes are larger in size.
 Mosquito cycle
A definitive Host – Mosquito
 Mosquito cycle
Sexual cycle
Sexual cycle will be initiated in the Humans by
the formation of Gametocytes
Develop further in the female Anopheles
Mosquito
Only mature sexual forms are capable of further
development in Mosquito
In midgut one Microgametocyte develops into 4-
8 thread like filamentous structures named Micro
gametes
From one macrogametocyte only one
macrogamete is formed
 Events in Mosquitos
Fertilization occurs when a
Microgametocyte penetrate into
Macrogametocyte
Fertilized macrogametocyte is known as
ZYGOTE
ZYGOTE matures into OOKINETE
OOKINETE to OOCYST
 Formation of Sporozoites in
Mosquitos.
OOCYST matures with large number of
Sporozoites ( A few hundred to thousands.)
OOCYST ruptures and release SPOROZOITES
in the body cavity of Mosquito
There is a specific predilection for salivary
glands
Now capable to transmit the infection to new
Host
Pathology and Pathogenesis

Sporozoites result from sexaul and

sporogenic cycle of development in
mosquitoes and injected into human blood
serum.
Events start with bite of Infected
Anopheles Mosquitoes
Sporoozoites enter liver, in 1 hour infect
the parenchymal cell.
Pathogenesis in Pre Erythrocyte
cycle
Numerous asexual progeny – Merozoites
ruputure and leave from liver cells
Enter the Blood and invade Erythrocytes
Erythrocytic cycle starts – Multiply in
species specific fashion
Broods of Merozoites appearing at 48
hour interval in P.ovale, P.vivax ,
P.falciparum
P.malariae appear in 72 hour cycles,
 Erythrocyte cycle
Merozoites released invade red cells
P.vivax infects young erythrocytes
P.malariae Infects old erythrocytes
P.falciparum infects RBC of all ages
The Merozoites are pear shaped 1-5
microns in length
The receptors for Merozoites are on red
cells in the glycoprotein
 Chooses to enter the RBC
Specific for each species
They pit on red cells
By endocytosis enters the RBC
Becomes a Trophozoites
 What happens in RBC
Size of Trophozoites is 1/3 of the RBC
except in P.falciparum which is 1/5 of
RBC
Feed on Hemoglobin but donot totally
metabolize and forms the Malarial pigment
 Schizont

When the Trophozoite is fully developed

becomes compact.
Malarial pigments are scattered through
the cytoplasm
The Nucleus is large and lies at the
periphery starts dividing.
Becomes Schizont
 Schizont
Schizont’s are 9 -10 microns
Divide and produce 8-32 Merozoites
Arranged in Rossets in two rows.
Mature schizonts rupture and release
Merozoites
Causes the paroxysms of fever.
Merozoites invade fresh RBC \ Cycles
repeats
 Cycles differs in Different
species

Cycle repeats every 48 hours in

1 P.falciparum
2 P.ovale
3 P.vivax
Repeats every 72 hours In
P.malariae
 Incubation period varies
according to species
Which includes Exo eythrocytic cycle time
and one or two erythocytic cycles,
P.vivax and P.falciparum 10 – 15 days
(can vary from weeks to months)
P.malariae infection can start after 28
days.
Clinical Features of
Malaria
 Clinical Manifestations are
related to cycle of events in
relation to RBC
What are the characteristics of a
malaria attack

Fever and shivering. The attack begins

with fever, with the temperature rising as
high as 40ºC and falling again over a
period of several hours.
A poor general condition, feeling unwell
and having headaches like influenza.
Diarrhea, nausea and vomiting often occur
as well.
 Clinical events
The symptoms often associated with
malaria are due to bursting red blood cells
and clogged capillaries of major organs.
Infection occurs when an infected
anopheles mosquito feeds on an
individual releasing sporozites into the
blood stream. Mosquitos can carry more
than one species and thus can infect
peoples with more than one species
Broad clinical manifestations of
Malaria
Fever
Sweating
Anemia
Splenomagaly (enlarged spleen)
Irratability
Coma, Retinal Hemorrages
Algid Malaria ( a shocklike syndrome)
Respiratory distress syndrome
 Cerebral Malaria

Malignant malaria can affect the brain and

the rest of the central nervous system. It is
characterized by changes in the level of
consciousness, convulsions and paralysis.
 Cerebral Malaria

Present with
Hyperpyrexia
Can lead to Coma
Paralysis and other
complications.
Brain appears
congested
 Black water fever

In malignant malaria a large number of the

red blood corpuscles are destroyed.
Hemoglobin from the blood corpuscles is
excreted in the urine, which therefore is
dark and almost the color of cola.
How long Malaria infection can
lost in Man
Without treatment P.falciparum will
terminate in less than 1 year.
But in P.vivax and P.ovale persist as
hypnozoites after the parasites have
disppeared from blood.
Can prodce periodic relapses upto 5 years
In P.malariae may last for 40 years
( Called as recrudescence X relapse )
Parasites survive in erythrocytes Liver ?
Why Falciparum Infections are
Dangerous
Can produce fatal complications,
1.Cerebral malaria
2.Malarial hyperpyrexia
3.Gastrointestinal disorders.
4.Algid malaria
5 Black water fever can lead to death
Complication of P.malariae

Can produce
Nephrotic syndrome
Affects mainly
children of years age
 Pernicious Malaria
Carries a High Mortality
On few occasions life
threading complications
can occur.
Occurs in infections with
P.falciparum
Associated with Heavy
parasitaztion
Grouped into three types
1. Cerebral Malaria
2 Algid malaria
3 Black water fever
How Malaria present Clinically
Stage 1
Chills for 15 mt to 1 hour
Caused due to rupture from the host red
cells escape into Blood
Preset with nausea, vomitting,headache
 Stage 2
Fever may reach upto 400c may last for
several hours starts invading newer red
cells.
 Clinical Malaria
Stage 3
patent starts sweating, concludes the
episode
Cycles are frequently Asynchronous
Paroxysms occur every 48 – 72 hours
In P.malariae pyrexia may lost for 8 hours or
more and temperature my exceed 410c
 Systemic Manifestations
Hepatomegaly
Splenomegaly
A.normocytic anemia devlops due
repeated ruputure of RBC’s
Laboratory Diagnosis
of Malaria
 Laboratory Diagnosis
Laboratory diagnosis of malaria can be
made through microscopic examination of
thick and thin blood smears. Thick blood
smears are more sensitive in detecting
malaria parasites because the blood is
more concentrated allowing for a greater
volume of blood to be examined; however,
thick smears are more difficult to read
Blood collected with sterile
technique
Making of Thick smear
How a thick smear looks
Appearance of Thick and Thin
Smears
 Microscopy
Malaria parasites can be identified by
examining under the microscope a drop of
the patient's blood, spread out as a "blood
smear" on a microscope slide. Prior to
examination, the specimen is stained
(most often with the Giemsa stain) to give
to the parasites a distinctive appearance.
This technique remains the gold standard
for laboratory confirmation of malaria
Microscopic demonstration still
the Gold standard in Diagnosis

Blood smear
stained with
Giemsa’s stain
 QBC system has evolved as
rapid and precise method in
Diagnosis
The QBC Malaria method is the simplest and
most sensitive method for diagnosing the
following diseases.

Malaria
 Babesiosis
 Trypanosomiasis (Chagas disease, Sleeping
Sickness)
 Filariasis (Elephantiasis, Loa-Loa)
 Relapsing Fever (Borreliosis)
Principle of QBC System
Appearance of Malarial parasite
in QBC system
Antigen Detection Methods are
Rapid and Precise
Antigen Detection
Various test kits are available to detect antigens
derived from malaria parasites. Such
immunologic ("immunochromatographic") tests
most often use a dipstick or cassette format, and
provide results in 2-15 minutes. These "Rapid
Diagnostic Tests" (RDTs) offer a useful
alternative to microscopy in situations where
reliable microscopic diagnosis is not available.
Malaria RDTs are currently used in some clinical
settings
 Serology

Serology detects antibodies against

malaria parasites, using either indirect
immunofluorescence (IFA) or enzyme-
linked immunosorbent assay (ELISA).
Serology does not detect current infection
but rather measures past experience.
Newer Diagnostic methods
Molecular Diagnosis

Parasite nucleic acids are detected using

polymerase chain reaction (PCR). This
technique is more accurate than
microscopy. However, it is expensive, and
requires a specialized laboratory (even
though technical advances will likely result
in field-operated PCR machines).
Other Laboratory Findings
Normocytic anemia of variable severity.
Liver function tests may be abnormal
Presence of protein and casts in the Urine
of children with P.malariae is suggestive of
Quartan nephrosis.
In severe Falciparum malaria with renal
damage may cause oliguria and
appearance of casts, protein, and red cells
in the Urine
 Treatment
Still the Choroquine continues to be Drug of
choice in all forms of susceptible in all forms of
Acute Malaria
1.5 grams of Chloroquine ( Base ) in over 3 days
peroid in adults
1.8 grams of Chloroquine in over 4 days.
In children dose to be calculated according to
weight
In cases of P.falcipqrum leading to coma need
to be treated with Quinidine gluconate till the oral
treatment is feasible.
 Treatment (cont)
P.vivax with Chloroquine resistance is on
raise But Chloroquine is preferred till drug
resistance is established.
Early decisions on P.falciparum treatment
with appropriate drug is highly essential in
view of the rapid detoriation with
complications.
 Radical Cure
Primaquin and 8 Aminoquilone eliminates
Exoeythrocytic forms ( Relapsing forms )
Individuals deficient in Glucose -6
phosphate dehydrogenase with Primaquin
treatment leads to hemolytic
complications. Avoid use of Primaquin or
give in low doses
People living in Eastern Mediterrian
regions or Some Blacks are prone.
 Treating Drug Resistance in
P.falciparum
Should be treated with
Quinine sulphate plus single dose of
Combination Drug Pyramethamine and
Sulphodoxine ( Fansidar )
Other Alternatives
1 Quinine plus Doxycycline or Tetracycline
2 Quinine plus Clindamycin
Newer alternatives
1 Mefloquine and Halofantril.
 Suppressive Prophylaxis
Popular drugs include, Chloroquine,
Amodiaquine.
Mefloquine is drug of choice in
Chloroquine resistant areas of the world
Prophylactic drugs are chosen on the
basis of scientific studies on resistance,
availaility,and individual accepatability
 CDC – on Current
Recommendations

The current guidelance on issues

related to Malaraia prevention can be
searched at
http://www.cdc.gov ( travelers health )
 Epidemiology
Malaria continues to be one of the most
important and devastating infectious
diseases in developing areas of the world.
Worldwide, over 40% of the population
lives in areas where malaria transmission
occurs (i.e., parts of Africa, Asia, the
Middle East, Central and South America,
Hispaniola, and Oceania)
Major cause of Morbidity and
Morality
1 It is estimated that 300-500 million cases
of malaria occur each year resulting in
7,50,000-2 million deaths.
 Control of Malaria

Elimination of Mosquito breeding places,

National improvements on health and
Hygiene.
Use of Mosquito nets, treated with
Pyrithrin
Clothing with sleeves, and long trousers
Use of Mosquito repellents
 Vaccines for Malaria
This degree of protection would be extremely
difficult to achieve and might not be technically
feasible with current vaccinology art and
science. Many vaccine developers have
therefore focused their efforts on creating a
vaccine that limits the ability of the parasite to
successfully infect large numbers of red blood
cells. This would not prevent infection but would
limit the severity of the disease and help prevent
malaria deaths.…Vaccine Challenges
 Current Initiatives
The PATH Malaria Vaccine Initiative and
partner, GlaxoSmithKline Biologicals,
published recent Phase 2 trial results
showing that the vaccine candidate,
RTS,S, has a promising safety and
tolerability profile and reduces malaria
parasite infection and clinical illness due to
malaria. This was the first RTS,S vaccine
trial in African infants.
 Current successful Trails
The most successful candidate developed to
date is the RTS,S recombinant vaccine. The
RTS,S/AS02A, one of the key vaccines
produced using this technique, has been used in
field trials in The Gambia. Three repeat doses
were administered in the 6 months leading up to
the period of highest malaria transmission. The
vaccine efficacy was reported at approximately
71% (with 95% confidence intervals spanning
from 46 to 85%) during the first 2 months of
follow-up, but falling to 0% in the last 6 weeks in
250 male volunteers.
 World Malaria Day
World Malaria Day (previously Africa
Malaria Day) will now be commemorated
every year on 25 April. The declaration of
the 2008 1st World Malaria Day reflects
the emphasis the world now attaches to
the burden of this disease and its impact
on the lives of those who live in malaria
endemic countries, especially children
under five years and pregnant women
Bill Gates greatest contribution
to Malaria eradication
The Bill & Melinda Gates Foundation
announced three grants totaling $258.3
million in 2005 for advanced development
of a malaria vaccine, new drugs, and
innovative mosquito control methods to
help defeat malaria, a disease that kills
2,000 African children every day
Bill Gates and Melinda Gates
contribution is Immense – In
Malaria
Created for Universal
Education on Malaria
Dr.T.V.Rao MD
Email
tvraodoctor2000@yahoo.co.in