MalariaRevisiting Malaria on World Malaria day 2023

1. Malaria
Revisiting Malaria on
World Malaria day
2023
Dr.T.V.Rao MD
Dr.T.V.Rao MD @ Malaria update 1

2. WORLD MALARIA DAY
World Malaria Day, marked each
year on 25 April, brings together
the global malaria community to
highlight global efforts to end
malaria, the need for sustained
political commitment and
continued investment for malaria
control and elimination.
Dr.T.V.Rao MD @ Malaria update 2

3. What is the theme of Malaria
Day 2023?
World Malaria Day
2023 will be
marked under the
theme “Time to
deliver zero
malaria: invest,
innovate,
implement”
Dr.T.V.Rao MD @ Malaria update 3

4. The World at Risk of
Malaria
Roughly half of the world’s
population is at risk of malaria.
According to the World Health
Organization (WHO), about 3.4
billion people are at risk of malaria.
WHO estimates that there were
about 207 million cases of malaria
and an estimated 627,000 deaths in
2012. Dr.T.V.Rao MD @ Malaria update 4

5. Malaria – Early History
The symptoms of
malaria were
described in ancient
Chinese medical
writings. In 2700 BC,
several characteristic
symptoms of what
would later be named
malaria were
described in the Nei
Ching,
Dr.T.V.Rao MD @ Malaria update 5

6. 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.
Dr.T.V.Rao MD @ Malaria update 6

7. 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,
Dr.T.V.Rao MD @ Malaria update 7

8. Malaria-endemic Areas 2000
Dr.T.V.Rao MD @ Malaria update 8

9. 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.
Dr.T.V.Rao MD @ Malaria update 9

10. 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.
Dr.T.V.Rao MD @ Malaria update 10

11. 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
Dr.T.V.Rao MD @ Malaria update 11

12. 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
Dr.T.V.Rao MD @ Malaria update 12

13. Charles Louis Alphonse Laveran,
Charles Louis Alphonse
Laveran, a French army
surgeon stationed in
Constantine, Algeria, was
the first to notice
parasites in the blood
of a patient suffering
from malaria. This
occurred on the 6th of
November 1880. For his
discovery, Laveran was
awarded the Nobel Prize
in 1907.
Doctortvrao’s ‘e’ learning series
Dr.T.V.Rao MD @ Malaria update 13

14. Ronald Ross
In August 20th, 1897,
Ronald Ross, a British
officer in the Indian
Medical Service, was the
first to demonstrate that
malaria parasites could
be transmitted from
infected patients to
mosquitoes For his
discovery, Ross was
awarded the Nobel
Prize in 1902.
Doctortvrao’s ‘e’ learning series
Dr.T.V.Rao MD @ Malaria update 14

15. 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.
Dr.T.V.Rao MD @ Malaria update 15

16. Chloroquine (Resochin) (1934,
1946)
Chloroquine was discovered by a German, Hans
Andersag, in 1934 at Bayer I.G. Farbenindustrie
A.G. laboratories in Eberfeld, Germany. He
named his compound resochin. Through a
series of lapses and confusion brought about
during the war, chloroquine was finally
recognized and established as an effective and
safe antimalarial in 1946 by British and U.S.
Doctortvrao’s ‘e’ learning series
Dr.T.V.Rao MD @ Malaria update 16

17. Malaria a vector borne Disease
Malaria is a vector-
borne infectious
disease caused by
protozoan parasites.
It is widespread in
tropicl and subtropical
regions, including
parts of the Americas,
Asia, and Africa.
Dr.T.V.Rao MD @ Malaria update 17

18. Female Anopheles Mosquitos
transmit Malaria
Dr.T.V.Rao MD @ Malaria update 18

19. 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
Dr.T.V.Rao MD @ Malaria update 19

20. Newer species
A fifth species,
Plasmodium
knowlesi, causes
malaria in macaques
but can also infect
humans.
Doctortvrao’s ‘e’ learning series
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21. SPOROZOA
SPOROZOA belong to phylum Apicomplexa –
contains two classes
1 Haematozoea
2 Coccidea
Belong to class Haematozoea occur in the blood
of the vertebrate hosts
contain two orders Haemosporidia (genus
Plasmodium – Malaria )
Piroplasmidia (containing genus Babesia)
Doctortvrao’s ‘e’ learning series
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22. Structure of Malarial
parasite
Dr.T.V.Rao MD @ Malaria update 22

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24. 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 .
Doctortvrao’s ‘e’ learning series
Dr.T.V.Rao MD @ Malaria update 24

25. A complex Life cycle
Dr.T.V.Rao MD @ Malaria update 25

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27. Human Cycle
1 Pre erythrocytic
schizogony
2 Erythrocytic
Schizogony
3 Gametogony
4 Exoerythrocytic
schizogony
Doctortvrao’s ‘e’ learning series
Dr.T.V.Rao MD @ Malaria update 27

28. 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.
Doctortvrao’s ‘e’ learning series
Dr.T.V.Rao MD @ Malaria update 28

29. 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
Doctortvrao’s ‘e’ learning series
Dr.T.V.Rao MD @ Malaria update 29

30. 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.
Doctortvrao’s ‘e’ learning series
Dr.T.V.Rao MD @ Malaria update 30

31. Exo-
erythrocytic
(hepatic) cycle
Sporozoites
Mosquito Salivary
Gland
Malaria Life
Cycle
Life Cycle
Gametocytes
Oocyst
Erythrocytic
Cycle
Zygote
Schizogony
Sporogony
Hypnozoites
(for P. vivax
and P. ovale)
Dr.T.V.Rao MD @ Malaria update 31

32. Exo-erythrocytic (tissue)
phase
P. malariae or P. falciparum
sporozoites do not form hypnotizes,
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 @ Malaria update 32

33. 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
Dr.T.V.Rao MD @ Malaria update 33

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35. 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
Doctortvrao’s ‘e’ learning series
Dr.T.V.Rao MD @ Malaria update 35

36. Erythrocytic Schizogony
Liberated Merozoites
penetrate RBC
Three stages occur
1 Trophozoites
2 Schizont
3 Merozoite
Dr.T.V.Rao MD @ Malaria update 36

37. 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
Dr.T.V.Rao MD @ Malaria update 37

38. Trophozoites
After invasion grow
and feed on
hemoglobin
Blue cytoplasm and
red nucleus, Called
as Signet ring
appearance
Hence called ring
form
Dr.T.V.Rao MD @ Malaria update 38

39. 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
Doctortvrao’s ‘e’ learning series
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40. Plasmodium vivax
Number of merozoites 12 to 24
arranged in grape like clusters
RBC enlarged
Schuffner’s dots present
Yellowish brown fine granules
Schizont 9-10 microns fills and
enlarged Red cell
Gametocytes – spherical or
globular
Size much larger than red cell
Male 9 microns
Female 10 – 11 microns
Doctortvrao’s ‘e’ learning series
Dr.T.V.Rao MD @ Malaria update 40

41. Plasmodium falciparum
RBC is normal size
Maurer’s dots 9 large
red spots sometimes
basophilic stippling
Dark brown or blackish
one or two solid blocks
Gametocytes Crescentric,
larger than a red cell 9 -
10 microns, male and
female 12- 14 microns
Dr.T.V.Rao MD @ Malaria update 41

42. Plasmodium malaria
RBC Normal size
Contain Ziemann’s
stippling
Contain dark brown
coarse granules
Schizont – 6 – 7 microns
almost fills a normal sized
red cell.
Gametocytes Spherical or
globular
Size much larger than a
red cell
Dr.T.V.Rao MD @ Malaria update 42

43. Plasmodium ovale
Infected RBC slightly
larger
Contain Schuffner’s dots
coarse granules
Schizont 6.2 microns fills
three quarters
Merozoites 6 -12 fills
three quarters
Gametocytes Spherical or
globular, much larger
than a red cell
Doctortvrao’s ‘e’ learning series
Dr.T.V.Rao MD @ Malaria update 43

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54. Exo-erythrocytic (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 @ Malaria update 54

55. 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
Doctortvrao’s ‘e’ learning series
Dr.T.V.Rao MD @ Malaria update 55

56. 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.
Dr.T.V.Rao MD @ Malaria update 56

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58. Mosquito cycle
A definitive Host – Mosquito
Dr.T.V.Rao MD @ Malaria update 58

59. 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
Dr.T.V.Rao MD @ Malaria update 59

60. Events in Mosquitos
Fertilization occurs when a
Microgametocyte penetrate into
Macrogametocyte
Fertilized macrogametocyte is known as
ZYGOTE
ZYGOTE matures into OOKINETE
OOKINETE to OOCYST
Dr.T.V.Rao MD @ Malaria update 60

61. 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
Doctortvrao’s ‘e’ learning series
Dr.T.V.Rao MD @ Malaria update 61

62. 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.
Dr.T.V.Rao MD @ Malaria update 62

63. 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.
Dr.T.V.Rao MD @ Malaria update 63

64. 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,
Dr.T.V.Rao MD @ Malaria update 64

65. Chooses to enter the RBC
Specific for each
species
They pit on red cells
By endocytosis enters
the RBC
Becomes a
Trophozoites
Dr.T.V.Rao MD @ Malaria update 65

66. 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
Doctortvrao’s ‘e’ learning series
Dr.T.V.Rao MD @ Malaria update 66

67. 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
Doctortvrao’s ‘e’ learning series
Dr.T.V.Rao MD @ Malaria update 67

68. 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.
Doctortvrao’s ‘e’ learning series
Dr.T.V.Rao MD @ Malaria update 68

69. Clinical Features of
Malaria
Dr.T.V.Rao MD @ Malaria update 69

70. Clinical Manifestations are
related to cycle of events in
relation to RBC
Dr.T.V.Rao MD @ Malaria update 70

71. 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.
Dr.T.V.Rao MD @ Malaria update 71

72. 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
Doctortvrao’s ‘e’ learning series
Dr.T.V.Rao MD @ Malaria update 72

73. More commonly, the patient presents
with a combination of the following
symptoms
Fever
Chills
Sweats
Headaches
Nausea and vomiting
Body aches
General malaise.
Doctortvrao’s e learning
Dr.T.V.Rao MD @ Malaria update 73

74. Early symptoms
The common first symptoms –
fever, headache, chills and
vomiting – usually appear 10 to 15
days after a person is infected. If
not treated promptly with effective
medicines, malaria can cause
severe illness and is often fatal.
Dr.T.V.Rao MD @ Malaria update 74

75. 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.
Doctortvrao’s ‘e’ learning series
Dr.T.V.Rao MD @ Malaria update 75

76. Malaria the disease
9-14 day
incubation
period
Fever, chills,
headache, back
and joint pain
Gastrointestinal
symptoms
(nausea,
vomiting, etc.)
Dr.T.V.Rao MD @ Malaria update 76

77. 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
Doctortvrao’s ‘e’ learning series
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78. Malaria stages of the disease
Dr.T.V.Rao MD @ Malaria update 78

79. Malaria intensifies
Symptoms intensify
Irregular high fever
Anxiety, delirium and
other mental problems
Sweating, increased
pulse rate, severe
exhaustion
Worsening GI symptoms
Enlarged spleen and liver
Dr.T.V.Rao MD @ Malaria update 79

80. Broad clinical manifestations of
Malaria
Fever
Sweating
Anemia
Splenomagaly (enlarged spleen)
Irratability
Coma, Retinal Hemorrages
Algid Malaria ( a shocklike syndrome)
Respiratory distress syndrome
Dr.T.V.Rao MD @ Malaria update 80

81. Periodicity can be clue in
Diagnosis and species relation
Malaria tertiana:
48h between fevers
(P. vivax and ovale)
Malaria quartana:
72h between fevers
(P. malariae)
Malaria tropica:
irregular high fever
(P. falciparum)
Dr.T.V.Rao MD @ Malaria update 81

82. Malaria the disease
Dr.T.V.Rao MD @ Malaria update 82

83. Pathogenesis of Malaria
In highly endemic
areas: high mortality
among children due to
severe anemia, children
who survive beyond the
first years show
decreasing parasitemia
and disease (this
immunity is not sterile
and depends on
constant exposure)
Doctortvrao’s ‘e’ learning series
Dr.T.V.Rao MD @ Malaria update 83

84. Cytokines & toxins
Hatched=chill
Black=rigor
Clear=sweating
 Malaria produces a strong
Th-1 type response
 Elevated serum levels of
IFNg and TNFa
 Cytokines can induce
(mimic) many of the
symptoms and signs of
malaria (shivering,
headache, chills, spiking
fever, sweating,
vasodilation, hypoglycemia)
Dr.T.V.Rao MD @ Malaria update 84

85. 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.
Dr.T.V.Rao MD @ Malaria update 85

86. Cerebral Malaria
Present with
Hyperpyrexia
Can lead to Coma
Paralysis and other
complications.
Brain appears
congested
Dr.T.V.Rao MD @ Malaria update 86

87. Pathogenesis of
Cerebral malaria
 High cytokine levels could be toxic on their own
 High levels of cytokine also enhance the second process
thought to be responsible for cerebral malaria: sequestration
of infected RBCs
Dr.T.V.Rao MD @ Malaria update 87

88. Sequestration & cytoadherence
Rosetting (adhesion of
infected RBCs to other
RBCs) and clumping
(adhesion between
infected cells) was first
observed in in vitro culture
Rosetting was also found
in 50% of field isolates and
correlated strongly with the
severity of the observed
disease
Dr.T.V.Rao MD @ Malaria update 88

89. Sequestration &
cytoadherence
How do parasite proteins travel
to the surface of the RBC?
This is a considerable challenge
as RBC lack functional
secretory apparatus
Why do patients fail to mount
an effective immune response
against antigens that are
presented this prominently?
Dr.T.V.Rao MD @ Malaria update 89

90. Black Water Fever
In malignant malaria a large
number of the red blood
corpuscles are destroyed.
Haemoglobin from the blood
corpuscles is excreted in the
urine, which therefore is dark
and almost the colour of cola
Dr.T.V.Rao MD @ Malaria update 90

91. 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 ?
Doctortvrao’s ‘e’ learning series
Dr.T.V.Rao MD @ Malaria update 91

92. 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
Doctortvrao’s ‘e’ learning series
Dr.T.V.Rao MD @ Malaria update 92

93. Complication of P.malariae
Can produce
Nephrotic syndrome
Affects mainly
children of years age
Dr.T.V.Rao MD @ Malaria update 93

94. 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
Dr.T.V.Rao MD @ Malaria update 94

95. 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)
Doctortvrao’s ‘e’ learning series
Dr.T.V.Rao MD @ Malaria update 95

96. Malaria A Major Health problem
of Tropical countreis
Dr.T.V.Rao MD @ Malaria update 96

97. Pernicious Malaria
Is a life threatening complication in acute
falciparum malaria
It is due to heavy parasitization
Manifest with
1 Cerebral malaria – it presents with
hyperpyrexia, coma and paralysis. Brain is
congested
2 Algid malaria – presents with clammy skin
leading to peripheral circulatory failure.
Dr.T.V.Rao MD @ Malaria update 97

98. Complication in Malaria
Pulmonary edema (fluid buildup in the
lungs) or acute respiratory distress
syndrome (ARDS), which may occur even
after the parasite counts have decreased
in response to treatment
Abnormalities in blood coagulation and
thrombocytopenia (decrease in blood
platelets)
Cardiovascular collapse and shock
Dr.T.V.Rao MD @ Malaria update 98

99. Black water Fever
It is a manifestation of infection with P.falciparum
occuring in persons who have been previously
infected and have had been inadequate dose of
quinine
It is characterized by intravascular hemolysis
fever, and Haemoglobunuria
Cardiovascular collapse and shock
Abnormalities in blood coagulation and
thrombocytopenia (decrease in blood platelets)
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100. Other Complications In Malaria
Acute kidney failure
Hyperparasitemia, where more than 5% of
the red blood cells are infected by malaria
parasites
Metabolic acidosis (excessive acidity in
the blood and tissue fluids), often in
association with hypoglycemia
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101. Immunity
Influenced by
 Genetics
 Age
 Health condition
 Pregnancy status
 Intensity of transmission in region
 Length of exposure
 Maintenance of exposure
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102. Immunity
Innate
 Red cell polymorphisms associated with some
protection
Hemoglobin S sickle cell trait or disease
Hemoglobin C and hemoglobin E
Thalessemia – α and β
Glucose – 6 – phosphate dehydrogenase deficiency
(G6PD)
 Red cell membrane changes
Absence of certain Duffy coat antigens improves
resistance to P.v.
Dr.T.V.Rao MD @ Malaria update 102

103. Immunity
Acquired
 Transferred from mother to child
3-6 months protection
Then children have increased susceptibility
 Increased susceptibility during early childhood
Hyper- and holoendemic areas
 By age 5 attacks usually < frequent and severe
 Can have > parasite densities with fewer symptoms
Meso- or hypoendemic areas
 Less transmission and repeated attacks
 May acquire partial immunity and be at higher risk for
symptomatic disease as adults
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104. Immunity
Acquired
 No complete immunity
Can be parasitemic without clinical disease
 Need long period of exposure for induction
 May need continued exposure for maintenance
 Immunity can be unstable
Can wane as one spends time outside endemic
area
Can change with movement to area with different
endemicity
Decreases during pregnancy, risk improves with
increasing gravidity
Dr.T.V.Rao MD @ Malaria update 104

105. Laboratory Diagnosis
of Malaria
Dr.T.V.Rao MD @ Malaria update 105

106. Diagnostic Tools
for Human Infections with
Malaria
Blood film
examination
Serology - IFA
PCR
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107. Blood collected with sterile
technique
Dr.T.V.Rao MD @ Malaria update 107

108. Making the smears
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109. Making of Thick smear
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110. Thin and Thick smear
Dr.T.V.Rao MD @ Malaria update 110

111. Appearance of Thick and Thin
Smears
Dr.T.V.Rao MD @ Malaria update 111

112. 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
Doctortvrao’s ‘e’ learning series
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113. How parasites appear
Dr.T.V.Rao MD @ Malaria update 113

114. Dr.T.V.Rao MD @ Malaria update 114

115. Dr.T.V.Rao MD @ Malaria update 115

116. 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)
 Doctortvrao’s ‘e’ learning series
Dr.T.V.Rao MD @ Malaria update 116

117. QBC system
Dr.T.V.Rao MD @ Malaria update 117

118. Appearance of Malarial parasite
in QBC system
Dr.T.V.Rao MD @ Malaria update 118

119. 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
Dr.T.V.Rao MD @ Malaria update 119

120. 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.
Doctortvrao’s ‘e’ learning series
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121. 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).
Dr.T.V.Rao MD @ Malaria update 121

122. Types of Serological
Assays
Malaria
Antibody Detection
Indirect Fluorescent Antibody
Enzyme immunoassays
Antigen Detection
Immunochromatographic
Dr.T.V.Rao MD @ Malaria update 122

123. Antibody Detection
=
Antigen-antibody
complex
Patient’s serum
contains specific
and non-specific
antibodies
+
Antigen
Dr.T.V.Rao MD @ Malaria update 123

124. Antibody Detection
*-labeled antibody to
human antibody
+
Antigen-antibody-
*antibody
complex
=
Antigen-
antibody
complex
Dr.T.V.Rao MD @ Malaria update 124

125. Indirect Fluorescent Antibody
(IFA)
Microscope slide
Dr.T.V.Rao MD @ Malaria update 125

126. Enzyme Immunoassay
(EIA/ELISA)
_
+
enzyme
substrate
Dr.T.V.Rao MD @ Malaria update 126

127. ELISA
Dr.T.V.Rao MD @ Malaria update 127

128. Antigen Detection
Monoclonal
antibody
=
Antigen-antibody
complex
+
Antigen in
patient’s serum
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129. Antigen Detection
=
Antibody-antigen-
antibody
complex
+
Immobiliz
ed
monoclon
al
antibody
Antigen-antibody
complex
Dr.T.V.Rao MD @ Malaria update 129

130. Antigen Detection
Malaria Immunochromatographic
Dipstick
Optimal Assay
P. falciparum
specific
monoclonal
antibody
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131. Malaria IFA Test
Sensitivity = 98%
Specificity = 99.5%
Sulzer et al, Am J Trop Med Hyg 1969;18:199-205
Sulzer et al, Bull Wld Hlth Org 1971;45:375-379
Dr.T.V.Rao MD @ Malaria update 131

132. P malaria
Dr.T.V.Rao MD @ Malaria update 132

133. Malaria IFA Test
Initial detection of antibodies
Parasitemia precedes antibody
P. vivax 2-6 days
 P. falciparum and P. malariae 4-6
days
If parasitemia is suppressed by
treatment, may develop
detectable antibody
Dr.T.V.Rao MD @ Malaria update 133

134. Malaria IFA Test
Determination of Infecting
Species
Non-Immune
Samples drawn 0-14 days post
onset: Highest titer was to the
infecting species in 81%
Samples drawn 15-60 days
post onset: Highest titer was to
the infecting species in 96%
Dr.T.V.Rao MD @ Malaria update 134

135. Malaria IFA Test
Determination of Infecting
Species
Is possible in non-immune
individuals with primary
infection.
Is NOT possible in immune
individuals because their antibody
response reflects multiple
infections with multiple species.
Dr.T.V.Rao MD @ Malaria update 135

136. Malaria IFA Test
Antibody Persistence after Treatment
Non-Immunes (Vietnam Vets with
Pv)
53% IFA negative at 6 mo.
post-Rx
59% IFA negative at 12 mo.
post-Rx
Wilson et al, Am J Trop Med Hyg 1970;19:401-404
Dr.T.V.Rao MD @ Malaria update 136

137. Malaria IFA Test
Antibody Persistence after Treatment
Non-Immunes (Vietnam Vets with
Pv)
53% IFA negative at 6 mo.
post-Rx
59% IFA negative at 12 mo.
post-Rx
Wilson et al, Am J Trop Med Hyg 1970;19:401-404
Dr.T.V.Rao MD @ Malaria update 137

138. Sensitivity of Tools for
Diagnosis of Malarial
Infection
1. Most sensitive:
Antibody detection
2. PCR
3. Blood film
examination
Dr.T.V.Rao MD @ Malaria update 138

139. Diagnosis of
Untreated Acute Malaria
Blood film
examination
PCR
Dr.T.V.Rao MD @ Malaria update 139

140. Diagnosis of
Chronic Malaria
Screen with serology
If IFA positive:
May do blood film examination
May do PCR
Doctortvrao’s ‘e’ learning series
Dr.T.V.Rao MD @ Malaria update 140

141. Diagnosis of
Treated Recent Malaria
Serology
Blood film
examination
PCR
Dr.T.V.Rao MD @ Malaria update 141

142. Malaria Relapses
In P. vivax and P. ovale infections, patients
having recovered from the first episode of illness
may suffer several additional attacks ("relapses")
after months or even years without symptoms.
Relapses occur because P. vivax and P. ovale
have dormant liver stage parasites
("hypnozoites") that may reactivate. Treatment to
reduce the chance of such relapses is available
and should follow treatment of the first attack.
Dr.T.V.Rao MD @ Malaria update 142

143. Treatment
Dr.T.V.Rao MD @ Malaria update 143

144. Over view of Treatment options in
Malaria
Most drugs used in treatment are active against the
parasite forms in the blood (the form that causes
disease) and include:
Chloroquine
Sulfadoxine-pyrimethamine (Fansidar®)
Mefloquine (Lariam®)
Atovaquone-proguanil (Malarone®)
Quinine
Doxycycline
Artemisin derivatives (not licensed for use in the United
States, but often found overseas)
Dr.T.V.Rao MD @ Malaria update 144

145. In endemic areas, the World Health
Organization recommends that treatment
be started within 24 hours after the first
symptoms appear. Treatment of patients
with uncomplicated malaria can be
conducted on an ambulatory basis
(without hospitalization) but patients with
severe malaria should be hospitalized if
possible.
Doctortvrao’s ‘e’ learning series
Dr.T.V.Rao MD @ Malaria update 145

146. What is presumptive treatment?
Presumption - In an area with high transmission of
malaria, it should be presumed that ALL cases of fever
are due to malaria.
Treatment - First loading dose of Chloroquine should be
administered immediately after collecting the blood
specimen, even without waiting for its report.
If the fever is indeed malaria, this treatment alleviates
symptoms early, may be well before the test result is
available.
If it is malaria, Chloroquine also prevents the spread of
malaria by destroying the gametocytes of P. vivax (the
more common malaria).
If it is not malaria, nothing is lost, for Chloroquine at this
dose is safe and has no adverse effects!
Dr.T.V.Rao MD @ Malaria update 146

147. Radical treatment
Radical treatment is administration of Primaquin
to all confirmed cases of malaria.
In P. vivax malaria, 2 weeks' therapy with
Primaquin completely cures the infection in the
host by its tissue schizonticidal activity and
thereby prevents relapses.
In P. falciparum malaria, a single dose of
primaquine destroys the gametocytes, thereby
prevents the spread of the infection into the
mosquito.
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148. Use of Primaquin
Primaquine is active against the dormant
parasite liver forms (hypnozoites) and
prevents relapses. Primaquine should not
be taken by pregnant women or by people
who are deficient in G6PD (glucose-6-
phosphate dehydrogenase). Patients
should not take primaquine until a
screening test has excluded G6PD
deficiency.
Doctortvrao’s ‘e’ learning series
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149. Drug Resistance
Dr.T.V.Rao MD @ Malaria update 149

150. Choroquine Resistance
Chloroquine resistant P. falciparum
(CRPF) first developed independently in 3
to 4 foci in Southeast Asia, Oceania , and
South America in the late 1950's and early
1960's. Since then, Chloroquine resistance
has spread to nearly all areas of the world
where falciparum malaria is transmitted
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151. Chloroquine Resistance
Chloroquine resistant P. vivax (CRPV)
malaria was first identified in 1989 among
Australians living in or travelling to Papua
New Guinea. CRPV has also now been
identified in Southeast Asia, on the Indian
subcontinent, and in South America. Vivax
malaria, particularly from Oceania, also
exhibits decreased susceptibility to
primaquine.
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152. Testing Drug Resistance
There are 4 basic methods for testing malaria for
drug resistance: in vivo tests, in vitro tests,
molecular characterization, and animal models.
Of these, only the first 3 are routinely done
In vivo tests: In these tests, patients with clinical
malaria are given a treatment dose of an
antimalarials drug under observation and are
monitored over time for either failure to clear
parasites or for reappearance of parasites.
Doctortvrao’s ‘e’ learning series
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153. In vitro Testing
In vitro tests: In these tests, blood samples
from malaria patients are obtained and the
malaria parasites are exposed to different
concentrations of antimalarials drugs in
the laboratory. Some methods call for
adaptation of parasites to culture first,
while others put blood directly from
patients into the test system.
Dr.T.V.Rao MD @ Malaria update 153

154. Molecular Methods
Molecular characterization: For some
drugs (Chloroquine, SP and similar drugs,
atovaquone), molecular markers have
been identified that confer resistance.
Molecular techniques, such as polymerase
chain reaction (PCR) or gene sequencing
can identify these markers in blood taken
from malaria-infected patien
Dr.T.V.Rao MD @ Malaria update 154

155. Resistance to Chloroquine -
1960
Dr.T.V.Rao MD @ Malaria update 155

156. Resistance to Chloroquine - 1970
Dr.T.V.Rao MD @ Malaria update 156

157. Resistance to Chloroquine -
1980
Dr.T.V.Rao MD @ Malaria update 157

158. Resistance to Chloroquine -
2000
Dr.T.V.Rao MD @ Malaria update 158

159. Antimalarials Resistance - 1998
(excluding CQ)
SP, Mefloquine, Halofantrine,
Quinine
SP
Mefloquine
SP, Mefloquine
Dr.T.V.Rao MD @ Malaria update 160

160. Reports of Chloroquine Resistance
in P.vivax
1989
1990
1995
1995
1991
1995
Dr.T.V.Rao MD @ Malaria update 161

161. World Malaria Day, April 25
April 25 is World Malaria
Day, which
commemorates the date
in 2000 when 44 African
leaders committed to
cutting malaria deaths in
half by 2010. This year's
World Malaria Day theme
is "Counting Malaria Out."
How does CDC
contribute?
Dr.T.V.Rao MD @ Malaria update 162

162. CDC's malaria Web site offers telediagnosis
and treatment strategies
You can e-mail a
digital image to the
Centres for Disease
Control and
Prevention for
telediagnosis, and if
necessary download
guidelines for
treatment from its
new malaria Web site,
Dr.T.V.Rao MD @ Malaria update 163

163. Tele Net Working
Images of other
suspected parasitic
infections can be e-
mailed to the CDC's
Laboratory Identification
of Parasites of Public
Health Concern program
(www.dpd.cdc.gov/dpdx).
Doctortvrao’s ‘e’ learning series
Dr.T.V.Rao MD @ Malaria update 164

164. Development of Vaccines
Malaria vaccines in development include:
pre-erythrocytic or liver-stage vaccines
that aim to protect against the early stage
of malaria infection; blood-stage vaccines
that aim to reduce the severity of disease;
and transmission-blocking vaccines that
are intended to prevent mosquitoes that
fed on an infected person from spreading
malaria to new hosts.
Dr.T.V.Rao MD @ Malaria update 165

165. Future Ambitions
The malaria vaccine community aims to
license—by 2015—a first-generation vaccine
that has 50 percent efficacy against severe
disease and death, with protection lasting at
least one year without the need for boosting.
They also aim to license—by 2025—a second-
generation malaria vaccine that has a protective
efficacy of at least 80 percent against clinical
disease and with protection lasting for many
years without a booster.
Dr.T.V.Rao MD @ Malaria update 166

166. Dr.T.V.Rao MD @ Malaria update 167

167. Why vaccines are Difficult
No licensed vaccine against malaria currently
exists
The parasite has evolved a series of strategies
that allow it to confuse, hide, and misdirect the
human immune system.
The parasite changes through several life stages
even while in the human host, presenting a
different subset of molecules for the immune
system to combat at each stage.
Dr.T.V.Rao MD @ Malaria update 168

168. What WHO says on Malaria
Over the last 2 decades, significant
progress has been achieved
towards malaria elimination.
According to the latest World
malaria report, 27 countries had
fewer than 100 cases of the
disease in 2020, up from 6
countries in 2000.
Dr.T.V.Rao MD @ Malaria update 169

169. What WHO says on Malaria
Countries that have achieved at
least 3 consecutive years of zero
indigenous cases of malaria (a
case contracted locally with no
evidence of importation from
another endemic country) are
eligible to apply for the WHO
certification of malaria elimination
Dr.T.V.Rao MD @ Malaria update 170

170. What WHO says on Malaria
Since 2015, 11 countries have been
certified by the WHO Director-General as
malaria-free, including Maldives (2015),
Sri Lanka (2016), Kyrgyzstan (2016),
Paraguay (2018), Uzbekistan (2018),
Argentina (2019), Algeria (2019), El
Salvador (2021), China (2021) Azerbaijan
(2023) and Tajikistan (2023).
Dr.T.V.Rao MD @ Malaria update 171

171. Advances in New Treatments
Among the most interesting antimalarial
target proteins currently studied are
proteases, protein kinases, Plasmodium
sugar transporter inhibitor, aquaporin-3
inhibitor, choline transport inhibitor,
dihydroorotate dehydrogenase inhibitor,
isoprenoid biosynthesis inhibitor,
farnesyltransferase inhibitor and enzymes
are involved in lipid metabolism and DNA
replication. This review summarizes the
novel molecular targets and their inhibitors
for antimalarial drug development
approaches. Dr.T.V.Rao MD @ Malaria update 172

172. The First approved Vaccine
The first approved
vaccine for malaria is
RTS,S, known by the
brand name
Mosquirix. As of April
2022, the vaccine has
been given to 1
million children living
in areas with
moderate-to-high
malaria transmission
Dr.T.V.Rao MD @ Malaria update 173

173. WHO on Malaria Vaccine
The World Health
Organization
recommends widespread
use of the RTS,S/AS01
(RTS,S) malaria vaccine
among children in sub-
Saharan Africa and in
other regions with
moderate to high P.
falciparum malaria
transmission.
Dr.T.V.Rao MD @ Malaria update 174

174. WHO on Malaria Vaccine
The
recommendation is
based on results
from the ongoing
pilot programme in
Ghana, Kenya and
Malawi that has
reached more than
1 million children
since 2019. Dr.T.V.Rao MD @ Malaria update 175

175. Simple protective Measures
Dr.T.V.Rao MD @ Malaria update 176

176. There's no reason only poor people should get
malaria': The moment Bill Gates released jar of
mosquitoes at packed conference
Dr.T.V.Rao MD @ Malaria update 177

177. Bill and Melinda Gates Foundation that announced last
year it was donating £115 million to help develop a
vaccine for the deadly disease.
Dr.T.V.Rao MD @ Malaria update 178

178. Goal of Humanity
Dr.T.V.Rao MD @ Malaria update 179

179. References
WHO resources on Malaria basics and
Recent advances
CDC Updates on Malaria
NIH USA
Google open resources and Images on
Malaria
180
Dr.T.V.Rao MD @ Malaria update

180. Created for Medical and
Paramedical students in
Developing World
Dr.T.V.Rao MD
Email
doctortvrao@gmail.com
Dr.T.V.Rao MD @ Malaria update 181