Malaria

Teaching Basics
Dr.T.V.Rao MD

Dr.T.V.Rao MD

History of Malaria
One of the oldest known diseases.
King Tut died of malaria.
Malaria has been infecting humans for over 50,000 years.
References to malaria have been recorded for nearly 6000
years, starting in China.
Used to be common in Europe and North America.
First advances in malaria were made in 1880 by a French
army doctor named Charles Laveran.
He looked into infected red blood cells and discovered the
parasite was a protist. This was the first time a protist was
discovered to cause a disease.

Carlos Finlay discovered that mosquitoes

transmitted diseases.
Dr.T.V.Rao MD

Lavern and Ronald Ross

Pioneered the Events on
Malaria

Malaria History
who made it

Alphonse Laveran

Sir Patrick Manson

Sir Ronald Ross

Dr.T.V.Rao MD

Giovanni Grassi
4

It was discovered
more than 100 years
ago

A French army
doctor in Algeria
observed parasites
inside red blood
cells of malaria
patients and
proposed for the
first time that a
protozoan caused
Charles Louis Alphonse Laveran
disease
Dr.T.V.Rao MD

Ronald Ross discovers the role of

mosquitos and transmission

Ronald Ross discovered

that mosquitoes
transmitted malaria in
1898.
First effective medicine
was discovered by Pierre
Pelletier and Joseph
Caventou. This medicine
is called quinine, which
comes from the bark of
cinchona trees in Peru.
No effective vaccine: only
immunity is a result of
multiple infections.

Dr.T.V.Rao MD

Nature of parasite as
Drawn by Lavern

Malaria Hot spots

Geographic
distribution

Dr.T.V.Rao MD

Present
geographical distribution of malaria

Dr.T.V.Rao MD

Dr.T.V.Rao MD

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MALARIA

40% of the worlds population lives in

endemic areas
3-500 million clinical cases per year
1.5-2.7 million deaths (90% Africa)
increasing problem (re-emerging disease)
resurgence in some areas
drug resistance ( mortality)

causative agent = Plasmodium

species
protozoan parasite
member of Apicomplexa
4 species infecting humans

transmitted by anopholine
mosquitoes
Dr.T.V.Rao MD

P. falciparum
P. vivax
P. malariae
P. ovale
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Plasmodium species
which
infect humans
Plasmodium vivax (tertian)
Plasmodium ovale (tertian)
Plasmodium falciparum (tertian)
Plasmodium malariae (quartian)

What is Malaria?
Malaria is a parasite that enters the
blood.
This parasite is a protozoan called
plasmodium.
3 to 700 million people get malaria
each year, but only kills 1 to 2 million
40% of the worlds population lives in
malaria zones
Malaria zones are: Africa, India, Middle
East, Southeast Asia, Central and South
America, Eastern Europe, and the South
Pacific (slide 13).
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What determines the spread of

malaria?
Malaria spread
depends on:
Rainfall pattern
?
(How does this
affect mosquito
Types
of mosquitoes in the area
breeding?)
How close are people to the breeding
sites?
Some areas constantly have a high
rate of malaria.
Dr.T.V.Rao MD
Other areas have
malaria seasons

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Malaria Life
Cycle
Life Cycle

Sporogony
Oocyst
Sporozoites
Mosquito Salivary
Gland

Zygote

Exoerythrocytic
(hepatic) cycle

Gametocytes

Erythrocytic
Cycle

Schizogony

Hypnozoites
(for P. vivax
and P. ovale)

LIFE CYCLE OF MALARIA

Oocyst
Sporozoites
Zygote

Stomach Wall

Salivary Gland

Pre-erythrocytic
(hepatic) cycle

Gametocytes

Exo-erythrocytic
(hepatic) cycle

Erythrocytic
Cycle

Hypnozoites

Adapted from:

Malaria
Transmission Cycle

Exo-erythrocytic (hepatic) Cycle:

Sporozoites infect liver cells and
develop into schizonts, which release
merozoites into the blood

Sporozoires injected
into human host during
blood meal

Parasites
mature in
mosquito
midgut and
migrate to
salivary
glands

MOSQUITO

Parasite undergoes
sexual reproduction in
the mosquito

HUMAN

Some merozoites
differentiate into male or
female gametocyctes

Dormant liver stages

(hypnozoites) of P.
vivax and P. ovale
Erythrocytic Cycle:
Merozoites infect red
blood cells to form
schizonts

Components of the Malaria Life

Cycle
Sporogonic cycle

Infective Period
Mosquito bites
uninfected
person
Mosquito bites
gametocytemic
person

Mosquito Vector
Parasites visible

Prepatent Period

Human Host

Symptom onset
Recovery

Incubation Period
Clinical Illness

Malaria Burden
Clinical Manifestations

Infected
Mosquit
o

Infect
ed
Huma
n

Acut
e
febril
e
illnes
s

Chroni
c
effect
s

Pregnan
cy

Severe
illness

Anem
ia
Neurolog
ic/
cognitive
Developme
ntal

Fet
us
Matern
Dr.T.V.Rao
MD
al

Hypoglyce
mia
Anem
ia
Respirato
ry
distress
Cerebral
malaria

Impaired
growth
and
developm
ent

Low birth
weight
Acute
illness
Anemi
a

Deat
h

Malnutriti
on

Infant
mortality
Impaired
19
producti
vity

Malaria parasite (plasmodium)

Pathogen of malaria
P.vivax ; P.falciparum ;P.malariae ;
P.ovale
P.vivax ; P.falciparum are more
common
Plasmodium is a wide distribution
in many tropical or subtropical
regions of the world
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Malaria Vectors

Anopheles balabacensis

A. gambiae

A. freeborni

A. stephensi
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Characteristic of life cycle

Intermediate host : human

Final host : mosquito
Infective stage : sporozoite
Infective way : mosquito bite skin of human
Parasitic position : liver and red blood cells
Transmitted stage : gametocytes
Schizogonic cycle in red cells : 48 hrs/P.v
Sporozoite : tachysporozite and
bradysporozite
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Mosquitoes and Malaria

The spread of malaria
depends on the life cycle
of the mosquito.
Adult mosquitoes lay their
eggs on water.
The eggs hatch to become
larvae and then pupae,
before turning into adults.
Adult females mosquitoes
only live 2 to 4 weeks.
So you can reduce malaria
by attacking any of these
four stages of the
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mosquito.

Life Cycle
sporozoites injected during

mosquito feeding
invade liver cells
exoerythrocytic schizogony
(merozoites)
merozoites invade RBCs
repeated erythrocytic
schizogony cycles
gametocytes infective for
mosquito
fusion of gametes in gut
sporogony on gut wall in
hemocoel
sporozoites invade salivary
glands

Dr.T.V.Rao MD

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Invasive Stages
Merozoite
erythrocytes
Sporozoite
salivary glands
hepatocytes
Ookinete
epithelium
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Species Characteristics
PV

PO

PM

PF

Periodicity(hrs.)
48
50
72
48
Parasites/Ml
20-50
9-30
6-20
50-2000
RBC Age
Young
Young
Old
Any
Hyponozoite
Yes
Yes
No
No
Duration (yrs.)
1.5-5
1.5-5
3->50
1-2
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Morphology
Malarial parasite trophozoites are generally ring
shaped, 1-2 microns in size, although other
forms (ameboid and band) may also exist.
The sexual forms of the parasite (gametocytes)
are much larger and 7-14 microns in size.
P. falciparum is the largest and is banana
shaped, while others are smaller and round.

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EXO-ERYTHROCYTIC
S
HYPNOZOITES

GAMETOCYTES

ERYTHROCYTIC

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Exoerythrocytic (tissue)
phase
Blood is infected with sporozoites about
30 minutes after the mosquito bite
The sporozoites are eaten by
macrophages or enter the liver cells
where they multiply
pre-erythrocytic schizogeny
P. vivax and P. ovale sporozoites form
parasites in the liver called hypnozoites

Exoerythrocytic (tissue)
phase
P. malariae or P. falciparum
sporozoites do not form
hypnozites, develop directly into
pre-erythrocytic schizonts in the
liver
Pre-erythrocytic schizogeny takes
6-16 days post infection
Schizonts rupture, releasing
merozoites which invade red blood
cells (RBC) in liver

Dr.T.V.Rao MD

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Exoerythrocytic Schizogony
hepatocyte invasion
asexual replication
6-15 days
1000-10,000 merozoites
no overt pathology

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Hyponozoite Forms
some EE forms exhibit delayed
replication (ie, dormant)
merozoites produced months after
initial infection
only P. vivax and P. ovale

relapse = hypnozoite
recrudescence =
subpatentt

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Relapsing malaria
P. vivax and P. ovale hypnozoites
remain dormant for months
They develop and undergoe preerythrocytic sporogeny
The schizonts rupture, releasing
merozoites and produce clinical
relapse

IS IT FALCIPARUM?
WHAT DOES THE SMEAR SHOW?
>3% PARASITEMIA
MONOTONOUS SMALL RINGS
NO TROPHOZOITES OR SCHIZONTS
BANANA SHAPED GAMETOCYTES
MULTIPLY INFECTED CELLS
APPLIQUE FORMS
CELLS OF ALL SIZES INFECTED

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How the parasite appears in

blood smear

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P. falciparum Blood stages

Uninfected RBC

2 hr.

4 hr.

12 hr.
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Exoerythrocytic (tissue) phase

P. vivax and P. ovale

hypnozoites remain dormant

for months
They develop and undergoe
pre-erythrocytic sporogeny
The schizonts rupture,
releasing merozoites and
producing clinical relapse

Erythrocytic phase
stages of parasite in RBC
Trophozoites are early stages with ring
form the youngest
Tropohozoite nucleus and cytoplasm
divide forming a schizont
Segmentation of schizonts nucleus and
cytoplasm forms merozoites
Schizogeny complete when schizont
ruptures, releasing merozoites into blood
stream, causing fever
These are asexual forms

Erythrocytic phase
stages of parasite in RBC

Merozoites invade other RBCs

and schizongeny is repeated
Parasite density increases until
hosts immune response slows
it down
Merozoites may develop into
gametocytes, the sexual forms
of the parasite

erythrocytic schizogony
48 hr in Pf, Pv, Po
72 hr in Pm
gametocytes

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Gametocytogenesis
alternative to asexual replication
induction factors not known
drug treatment #'s
immune response #'s

ring gametocyte

Pf : ~10 days
others: ~same as schizogony

sexual dimorphism
microgametocytes
macrogametocytes

no pathology
infective stage for mosquito
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Gametocytes

Male gametocyte

Female gametocyte

Note: compact cytoplasm and absence of

nuclear division.
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Gametocyte of P. falciparum

banana shaped gametocyte

( P. falciparum)

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Gametogenesis
occurs in mosquito gut
exflagellation most
obvious
3X nuclear replication
8 microgametes formed

exposure to air induces

temperature (2-3oC)
pH (8-8.3)
result of pCO2

gametoctye activating
factor in mosquito
xanthurenic acid
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Sporogony

occurs in mosquito (9-21 d)

fusion of micro- and
macrogametes
zygote ookinete (~24 hr)
ookinete transverses gut
epithelium ('trans-invasion')

Dr.T.V.Rao MD

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Sporogony
ookinete oocyst

between epithelium and

basal lamina

asexual replication
sporozoites
sporozoites released

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Sporogony
sporozoites migrate
through hemocoel
sporozoites 'invade'
salivary glands

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Incubation Period
Following the infective bite by the
Anopheles mosquito a period of time
(the "incubation period") goes by
before the first symptoms appear.
The incubation period in most cases
varies from 7 to 30 days.
The shorter periods are observed
most frequently with P. falciparum and
the longer ones with P. malariae.
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Schizogenic periodicity and fever patterns

Schizogenic periodicity is length of

asexual erythrocytic phase
48 hours in P.f., P.v., and P.o. (tertian)
72 hours in P.m. (quartian)

Initially may not see characteristic fever

pattern if schizogeny not synchronous
With synchrony, periods of fever or
febrile paroxsyms assume a more
definite 3 (tertian)- or 4 (quartian)- day
pattern

Clinical
Features
characterized by acute febrile attacks (malaria
paroxysms)
periodic episodes of fever alternating with symptom-free
periods

manifestations and severity depend on species and host

status
immunity, general health, nutritional state, genetics

recrudescences and relapses can occur over months or

years

can develop severe complications

(especially P. falciparum)
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Malaria
Paroxysm
paroxysms associated with
synchrony of merozoite
release
between paroxysms temperature is normal and patient
feels well
falciparum may not exhibit
classic paroxysms
(continuous fever)
tertian malaria
quartan malaria
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Clinical manifestations
1
2
3
4

Anemia
Splenomegaly
Cerebral malaria
Malaria
nephropathy
5 Congenital malaria
usually fatal
6 black water fever

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Clinical presentation
Acute febrile illness, may have periodic
febrile paroxysms every 48 72 hours with
Afebrile asymptomatic intervals
Tendency to recrudesce or relapse over
months to years
Anemia, thrombocytopenia, jaundice,
hepatosplenomegaly, respiratory distress
syndrome, renal dysfunction,
hypoglycemia, mental status changes,
tropical splenomegaly syndrome

Clinical presentation
Early symptoms

Headache
Malaise
Fatigue
Nausea
Muscular pains
Slight diarrhea
Slight fever, usually not intermittent

Could mistake for influenza or

gastrointestinal infection

What are the signs and symptoms of malaria?

Symptoms of malaria include fever and

flu-like illness, including shaking chills,
headache, muscle aches, and tiredness.
Nausea, vomiting, and diarrhea may
also occur. Malaria may cause anemia
and jaundice (yellow coloring of the skin
and eyes) because of the loss of red
blood cells.
Infection with one type of malaria,
Plasmodium falciparum, if not promptly
treated, may cause kidney failure,
seizures, mental confusion, coma, and
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death.

Uncomplicated Malaria
The classical (but rarely observed)
malaria attack lasts 6-10 hours.
It consists of a cold stage
(sensation of cold, shivering) ; a
hot stage (fever, headaches,
vomiting; seizures in young
children) and finally a sweating
stage (sweats, return to normal
temperature, tiredness)
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IS IT FALCIPARUM?
WHAT DOES THE SMEAR SHOW?
>3% PARASITEMIA
MONOTONOUS SMALL RINGS
NO TROPHOZOITES OR SCHIZONTS
BANANA SHAPED GAMETOCYTES
MULTIPLY INFECTED CELLS
APPLIQUE FORMS
CELLS OF ALL SIZES INFECTED

Dr.T.V.Rao MD

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----a

Relapse

specific attack that it is up to months or

even years after the primary attacks.
----The bradysporozoites in the liver spend a rest
and sleeping times of months or even years ,
then they start develop in Exoerythrocytic stage
and erythrocytic stage. at this time, the patient
occurs paroxysm , showing as periodic fever like
the primary attacks, it is called relapse.
----Relapse

only occurs in P.vivax

less in P.ovale
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Malignant malaria
Malaria caused by P.falciparum. is
more severe than that caused by other
plasmodia.
----The serious complication of
P.falciparum. involves cerebral malaria
(involving the brain); massive
haemoglobinuria (blackwater fever) in
which the urine becomes dark in color,
because of acute hemolysis of RBC;
acute respiratory distress syndrome;
severe gastrointestinal symptoms; shock
Dr.T.V.Rao MD

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Laboratory diagnosis
laboratory diagnosis of malaria is
confirmed by the demonstration of
malarial parasites in
----

the blood film

under microscopic examination.
Thin film
Thick film
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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

Microscopic demonstration still

the Gold standard in Diagnosis

Blood smear
stained with
Giemsas
stain

Antigen Detection methods

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
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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

Serology in Malaria
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
exposure.
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Molecular Diagnosis of malaria

Parasite nucleic acids are

detected using polymerase
chain reaction (PCR).
Although this technique
may be slightly more
sensitive than smear
microscopy, it is of limited
utility for the diagnosis of
acutely ill patients in the
standard healthcare
setting. PCR results are
often not available quickly
enough to be of value in
establishing the diagnosis
of malaria infection.

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75

Newer Diagnostic methods

Molecular Diagnosi

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).

PCR is useful in species

detection
PCR is most useful
for confirming the
species of malarial
parasite after the
diagnosis has been
established by
either smear
microscopy or RDT.

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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
Faciparum?

Yes

Fansidar or
Artemeter/Lumefantrine

No

Vivax or Ovale

Chloroquine
Check G6PD
Primaquine

Dr.T.V.Rao MD

Malariae

Chloroquine

79

TREATMENT
HALOFANTRINE
MALARONE
ATOVAQUONE/PROGUANIL
TAFENOQUINE
QUININE based regimens
CHLOROQUINE/PROGUANIL IS AN INFERIOR
REGIMEN AND SHOULD NOT BE USED

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What are ways to

prevent mosquito bites?
Use mosquito
repellants.
Wear long pants
and long
sleeves.
Wear lightcolored clothes.
Use window
screens
Use bed nets.

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81

Insecticide-Treated Nets
(ITNs)
What is happening here?
What needs to happen within six months?
Can you think of any practical challenges?

Source: HEPFDC,
2009.

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82

Original Eradication Plans

Interruption of
transmission of
main species
infecting humans
by DDT spraying
Malaria
disappears
spontaneously in
under 3 years
Source: Gabaldon

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Other Ways to Prevent Malaria

Who is at the highest risk of malaria?
Travelers to an area high in malaria
Travelers often take prophylactic
(preventive) medicines to prevent
malaria.
Pregnant women (especially those with HIV)
Pregnant women are given intermittent
preventive treatment. They are given at
least 2 doses of a malaria drug during
their pregnancy.
Young children
How can you protect young children?
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84

Malaria Vaccine
Scientists are working on a new
malaria vaccine.
The vaccine would help protect
children from deadly malaria.
The vaccine boosts the immune
response against malaria.
However, the vaccine is still
being tested.
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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.

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 Dayreflects 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 underfive years

Created for Universal

Education on Malaria
Dr.T.V.Rao MD

Email
[email protected]