Submitted by Selma Abdul Samad BCH100502 S3 MScBiochemistry What is Malaria An infectious tropical Disease caused by the parasite Plasmodium sp in humans The name malaria derived from the Italian ID: 775355
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Slide1
MALARIA
Assignment on
BCH 514 Clinical Biochemistry
Submitted by
Selma Abdul
Samad
BCH-10-05-02
S3
MSc.Biochemistry
Slide2What is Malaria ??
An infectious tropical Disease caused by the parasite Plasmodium sp. in
humans
The name malaria derived from the Italian
mal’aria
or
bad air
Fifth cause of death from infectious diseases worldwide (after respiratory infections, HIV/AIDS, diarrhoeal diseases, and tuberculosis) and the second in Africa, after HIV/AIDS
It is a disease that can be treated in just 48 hours, yet it can cause fatal complications if the diagnosis and treatment are delayed.
Slide3Geographical Distribution
#1 priority tropical disease of WHO
Prevalent in 108 countries of the tropical and semitropical world (
home to half of the world
)
Every year, malaria is reported to cause more than 250-660 million infections and more than a million deaths (
mostly among African children
)
There has been a sharp decline in the incidence of malaria in South-East Asia since 1977 reflecting a rapid fall in India and Sri Lanka but . there has been a slow increase in South and Central America.
Slide4Geographical Distribution
Slide5Slide6In India ..
Orissa, Chhattisgarh, West Bengal, Jharkhand and Karnataka contribute the most number of cases of malaria in India
Slide7HISTORY OF MALARIA
One of the oldest diseases known to mankind
Wars , kings , dynasties etc influenced
Malaria was linked with poisonous vapours of swamps or stagnant water on the ground since time immemorial.
The word was introduced to English by Horace Walpole, who wrote in 1740 about a “horrid thing called
mal’aria
, that comes to Rome every summer and kills one.” The term malaria, without the apostrophe, evolved into the name of the disease only in the 20th . century.
Slide8Man and Malaria seem to have evolved together
It is believed that most, if not all, of today's populations of human malaria may have had their origin in West Africa (P.
falciparum
) and West and Central Africa (P.
vivax
) on the basis of the presence of homozygous alleles for
hemoglobin
C and RBC Duffy negativity that confer protection against P.
falciparum
and P.
vivax
respectively
Slide9Different studies have suggested that P.
falciparum
malaria probably jumped from great apes to man, probably by a single host transfer by vector mosquitoes
P.
malariae
, P.
ovale
, and P.
vivax
diverged over 100 million years ago along the lineage of the mammalian malaria parasites
P.
ovale
is the
the
sole known surviving representative of its line and causes infection only in humans
Slide10Famous victims of malaria
Alexander the Great is believed to have died of malaria in 323 BC, on the route to India beyond MesopotamiaGeorge Washington, (1st President of US, 1789-1797): Developed his first bout with malaria in Virginia in 1749 at age 17. He had periodic attacks, recorded in 1752, 1761, 1784, and 1798.Abraham Lincoln (16th President, 1861-1865) had periodic bouts of malaria when growing upJohn F. Kennedy (35th President, 1961-1963) acquired malaria during World War II, about 1943Mother Teresa was hospitalized with malaria in 1993, ……………….and many many others………………..
Slide11Scientific Discoveries…
Hippocrates was probably the the first malariologist The Hippocratic corpus was the first document to mention about splenic change in malaria and also it attributed malaria to ingestion of stagnant water
Slide12Time Line For Scientific Discoveries
Ancient Times - Early man attributed the fevers to evil spirits, angered deities, demons, or the black magic of sorcerers
Severel
thousand years ago - Babylonian cuneiform script attributes malaria to a god, pictured as a mosquito-like insect
800 BC - Indian sage
Dhanvantari
wrote that bites of mosquitoes could causes diseases, fever, shivering etc.
400 BC - Hippocrates described the various malaria fevers of man; distinguished the intermittent malarial fever from the other continuous fevers; noted the daily, every-other-day, and every-third-day temperature rise; mentioned about
splenic
change in malaria; attributed malaria to ingestion of stagnant water; also related the fever to the time of the year and to where the patients lived
Slide13Several theories and hypotheses came for years
It was finally in 1884 that Plasmodium was discovered by Russian Scientists and their link with malaria was confirmed by Louis Pasteur.In 1897 Ronald Ross demonstrated oocysts in the gut of anopheline mosquito at Secunderabad, India, proving that mosquito was the vector for malaria
Slide14Nobel Prizes for Malaria Related Research
Ronald Ross, 1902: "For his work on malaria, by which he has shown how it enters the organism and thereby has laid the foundation for successful research on this disease and methods of combating it". Ronald Ross demonstrated the oocyst of malarial parasite in the gut wall of a mosquito on August 20, 1897 in Secunderabad, India.Alphonse Laveran, 1907: "In recognition of his work on the role played by protozoa in causing diseases". Laveran was the first to notice parasites in the blood of a patient suffering from malaria on November 6, 1880 at Constantine, Algeria.
Slide15Julius Wagner-
Jauregg, 1927: "For his discovery of the therapeutic value of malaria inoculation in the treatment of dementia paralytica".Paul Hermann Müller, 1948: "For his discovery of the high efficiency of DDT as a contact poison against several arthropods".
Slide16Etiology
5 species of malaria parasites that infect man identified
Plasmodium
vivax
(
vivax
malaria, benign tertian malaria)
Plasmodium
ovale
(
ovale
malaria,
ovale
tertian malaria)
Plasmodium
malariae
(
quartan
malaria)
Plasmodium
falciparum
(
falciparum
malaria, malignant tertian malaria, pernicious malaria,
subtertian
malaria)
Plasmodium
knowlesi
Slide17The Malaria Parasites
Protozoan parasites called Plasmodia
Phylum: Protozoa
Class:
Sporozoa
Genus: Plasmodia
Species : several species, 5 known to affect man
Slide18Slide19Slide20INFECTION
TRANSMISSION
Principal mode of spread of malaria is by the bites of female
Anopheles
mosquito
Of more than 480 species
of
Anopheles
, only about 50 species transmit malaria
The habits of most of the
anopheline
mosquitoes have been characterised as
anthropophilic
(prefer human blood meal),
endophagic
(bite indoors), and nocturnal (bite at night) with peak biting at midnight, between 11 pm and 2 am.
Slide21The blood meal from a vertebrate host is essential for the female mosquitoes to nourish their eggs.
The mosquitoes find their host by seeking visual, thermal, and olfactory stimuli and of these, carbon dioxide, lactic acid, skin temperature, and moisture are more important mosquito attractantsWhen a mosquito bites an infected individual, it sucks the gametocytes, the sexual forms of the parasite, along with blood. These gametocytes continue the sexual phase of the cycle within the mosquito gut and the sporozoites that develop then fill the salivary glands of the infested mosquito. When this female mosquito bites another man for a blood meal, the sporozoites are inoculated into the blood stream of the fresh victim, thus spreading the infection.
Slide22Anopheles Mosquito
Malaria is transmitted from man to man by the female anopheles mosquito
Nearly 45 species of the mosquito have been found in IndiaHow does a mosquito bite?
Anopheles Mosquito
Slide23Other modes of transmission
Mother to the growing
fetus
(Congenital malaria) -
transplacentally
or during
labor
Transfusion Malaria:
transmitted by transfusion of blood from infected donors.
Needle stick injury:
accidentally among health care or due to needle sharing among drug addicts
Slide24LIFE CYCLE
The malaria parasite has a complex, multistage life cycle occurring within two living beings, the vector mosquitoes and the vertebrate hosts.
Consits
of two phases
Sexual phase (
sporogony
) – in female anopheles mosquito
Asexual phase (
schizogony
) – in man
Slide25The parasite passes through several stages of development such as the
sporozoites
(Gr.
Sporos
= seeds; the infectious form injected by the mosquito)
merozoites
(Gr.
Meros
= piece; the stage invading the erythrocytes)
trophozoites
(Gr.
Trophes
= nourishment; the form multiplying in erythrocytes) and
gametocytes (sexual stages)
all these stages have their own unique shapes and structures and protein complements.
The surface proteins and metabolic pathways keep changing during these different stages, that help the parasite to evade the immune clearance, while also creating problems for the development of drugs and vaccines
Slide26Sporogony Within the Mosquitoes
Mosquitoes are the definitive hosts for the malaria parasites, wherein the sexual phase(
sporogony
) of the parasite's life cycle occurs
Results in the development of innumerable infecting forms of the parasite within the mosquito that induce disease in the human host following their injection with the mosquito bite
Infected individual
mosquito draws blood
the male and female gametocytes of the parasite find their way into the gut of the mosquito
Female forms
macrogametes
; Males form microgamete
Slide27The male and female gametes fuse in the mosquito gut to form zygotes, which subsequently develop into actively moving
ookinetes
that burrow into the mosquito
midgut
wall to develop into
oocysts
.
Growth and division of each
oocyst
produces thousands of active haploid forms called
sporozoites
.
After the
sporogonic
phase of 8–15 days, the
oocyst
bursts and releases
sporozoites
into the body cavity of the mosquito, from where they travel to and invade the mosquito salivary glands.
Slide28When the mosquito thus loaded with
sporozoites
takes another blood meal, the
sporozoites
get injected from its salivary glands into the human bloodstream, causing malaria infection in the human host.
It has been found that the infected mosquito and the parasite mutually benefit each other and thereby promote transmission of the infection. The
Plasmodium
-infected mosquitoes have a better survival and show an increased rate of blood-feeding, particularly from an infected host.
The duration of the cycle in the mosquito is known as the external incubation period and varies from 8-10 days (28`C) to 16 days (20`C)
Slide29Malaria
oocysts
on stomach of mosquito
Slide30Schizogony in the Human Host
Man is the intermediate host for malaria, wherein the asexual phase of the life cycle occurs.
The
sporozoites
inoculated by the infested mosquito initiate this phase of the cycle from the liver, and the latter part continues within the red blood cells, which results in the various clinical manifestations of the disease.
Pre-
erythrocytic
Phase -
Schizogony
in the Liver:
With the mosquito bite, tens to a few hundred invasive
sporozoites
are introduced into the skin.
Following the
intradermal
deposition, some
sporozoites
are destroyed by the local macrophages, some enter the
lymphatics
, and some others find a blood vessel.
Slide31The
sporozoites
that enter a lymphatic vessel reach the draining lymph node wherein some of the
sporozoites
partially develop into
exoerythrocytic
stages and may also prime the T cells to mount a protective immune response
The
sporozoites
that find a blood vessel reach the liver within a few hours
The
sporozoites
then negotiate through the liver sinusoids, and migrate into a few
hepatocytes
, and then multiply and grow within
parasitophorous
vacuoles.
Each
sporozoite
develop into a
schizont
containing 10,000–30,000
merozoites
(or more in case of
P.
falciparum
.
The growth and development of the parasite in the liver cells is facilitated by a
a
favorable
environment created by the
The
circumsporozoite
protein of the parasite.
Slide32The entire pre-
erythrocytic
phase lasts about 5–16 days depending on the parasite species:
on an average 5-6 days for
P.
falciparum
,
8 days
for
P
.
vivax
,
9 days for
P.
ovale
,
13 days for
P.
malariae
and
8-9 days for
P.
knowlesi
.
The pre-
erythrocytic
phase remains a “silent” phase, with little pathology and no symptoms, as only a few
hepatocytes
are affected. This phase is also a single cycle, unlike the next,
erythrocytic
stage, which occurs repeatedly.
Slide33The
merozoites
that develop within the
hepatocyte
are contained inside host cell-derived vesicles called
merosomes
that exit the liver intact, thereby protecting the
merozoites
from
phagocytosis
by
Kupffer
cells.
These
merozoites
are eventually released into the blood stream at the lung capillaries and initiate the blood stage of infection thereon.
In
P.
vivax
and
P.
ovale
malaria, some of the
sporozoites
may remain dormant for months within the liver. Termed as
hypnozoites
, these forms develop into
schizonts
after some latent period, usually of a few weeks to months.
Slide34Erythrocytic
Schizogony
- Centre Stage in Red Cells
Red blood cells are the 'centre stage' for the asexual development of the malaria parasite.
Within the red cells, repeated cycles of parasitic development occur with precise periodicity, and at the end of each cycle, hundreds of fresh daughter parasites are released that invade more number of red cells.
The
merozoites
released from the liver recognize, attach, and enter the red blood cells (RBCs) by multiple receptor–
ligand
interactions in as little as 60 seconds. This quick disappearance from the circulation into the red cells minimises the exposure of the antigens on the surface of the parasite, thereby . protecting these parasite forms from the host immune response.
Slide35The invasion of the
merozoites
into the red cells is facilitated by molecular interactions between distinct
ligands
on the
merozoite
and host receptors on the erythrocyte membrane.
Glycophorin
, the major
erythrocytic
glycoprotein is involved in
merozoite
invasion.
The more virulent
P.
falciparum
uses several different receptor families and alternate invasion pathways that are highly redundant and hence can invade any red cell while others like
P.vivax
can invade using one type of receptor.
Slide36The process of attachment, invasion, and establishment of the
merozoite
into the red cell is made possible by the specialized apical
secretory
organelles of the
merozoite
, called the
micronemes
,
rhoptries
, and dense granules.
The initial interaction between the parasite and the red cell stimulates a rapid “wave” of deformation across the red cell membrane, leading to the formation of a stable parasite–host cell junction.
Following this, the parasite pushes its way through the erythrocyte
bilayer
with the help of the
actin
–myosin motor, proteins of the
thrombospondin
-related anonymous protein family (TRAP) and
aldolase
, and creates a
parasitophorous
vacuole to seal itself from the host-cell cytoplasm, thus creating a hospitable environment for its development within the red cell.
At this stage, the parasite appears as an intracellular “ring”.
Slide37Slide38The ring forms grow in size to
trophozoites
. Meanwhile, they
utilise
Hb
.
ie
., the amino acids are
utilised
for protein
bioshynthesis
and the toxic
heme
is detoxified by
heme
polymerase and sequestered as
hemozoin
(malaria pigment)
The parasite depends on anaerobic
glycolysis
for energy
The
trophozoite
multiplies by
schizogony
dividing into a number of small
merozoites
varying with the species to form a mature
schizont
.
The
erythrocytic
phase is called
schizogonic
periodicity
At the end of the
cycle,the
merozoites
are released by rupture of the red cell membrane and enter new red cells, particularly young red cells.
Slide39The
erythrocytic
cycle occurs every
24 hours in case of
P.
knowlesi
,
48 h in cases of
P.
falciparum
, P.
vivax
and
P.
ovale
and
72 h in case of
P.
malariae
.
During each cycle, each
merozoite
grows and divides within the vacuole into 8–32 (average 10) fresh
merozoites
, through the stages of ring,
trophozoite
, and
schizont
.
Slide40Gametogony
:
A small proportion of asexual parasites do not undergo
schizogony
but differentiate into the sexual stage gametocytes.
These male or female gametocytes are extracellular and
nonpathogenic
and help in transmission of the infection to others through the female
anopheline
mosquitoes, wherein they continue the sexual phase of the parasite's life cycle.
Gametocytes of
P.
vivax
develop soon after the release of
merozoites
from the liver, whereas in case of
P.
falciparum
, the gametocytes develop much later with peak densities of the sexual stages typically occurring 1 week after peak asexual stage densities.
Slide41Slide42Slide43Slide44PATHOLOGY
The most pronounced changes related to malaria involve the blood and the blood-forming system, the spleen and the liver.
Secondary changes can occur in all the other major organs, depending on the type and severity of the infection.
The pathological changes are more profound and severe in case of
P.
falciparum
malaria. Severe malaria is a complex multisystem disorder with many similarities to sepsis syndromes.
Slide45RBC rupture ;
cytoadherence
and sequestration
Anemia
Thrombocytopenia ; Clotting defects
Elevated ESR
Bone marrow may show evidence of
dyserythropoeisis
, iron sequestration and
erythrophagocytosis
in the acute phase of
falciparum
malaria
.
Splenomegaly
;
Splenic
rupture
Malarial hepatitis ;
Hepatomegaly
cardiovascular function abnormalities
Slide46GI irritation, ischemia, ulcers , necrosis
Nephritis ;
albuminuria
; kidney failure ; edema
CNS manifestations ( in
P.falciparum
)
All pathological manifestations increased and severe in case of
falciparum
malaria
Slide47CLINICAL FEATURES
All the clinical features of malaria are caused by the
erythrocytic
schizogony
in the blood
Typical features:
It includes three stages viz. Cold stage, Hot stage and Sweating stage
The febrile episode starts with shaking chills, usually at mid-day between 11 a.m. to 12 noon, and this lasts from 15 minutes to 1 hour (the cold stage)
Followed by high grade fever, even reaching above 106
0
F, which lasts 2 to 6 hours (the hot stage).
This is followed by profuse sweating and the fever gradually subsides over 2-4 hours. These typical features are seen after the infection gets established for about a week.
Slide48In
vivax
malaria, this typical pattern of fever recurs once every 48 hours and this is called as
Benign Tertian malaria.
Similar pattern may be seen in
ovale
malaria too
(
Ovale
tertian malaria)
.
In
falciparum
infection
(Malignant tertian
malaria),
this pattern may not be seen often and the paroxysms tend to be more frequent
(Sub-tertian).
In
P.
malariae
infection, the relapses occur once every 72 hours and it is called
Quartan
malaria.
Slide49Atypical features:
In an endemic area, malaria often presents with atypical manifestations
Atypical fever
Headache
Body ache, back ache and joint pains
Dizziness, vertigo
Altered behaviour, acute psychosis
Altered
sensorium
Convulsions, coma
Cough
Breathlessness
Chest pain
Slide50Acute abdomen
Weakness
Vomiting and diarrhoea
Jaundice
Pallor
Puffiness of lids
Secondary infections
Hepatosplenomegaly
Combinations of the above
Slide51Clinical features suggesting
P.
falciparum
infection:
Presence of any of the complications of
P.
falciparum
malaria viz. altered
sensorium
; convulsions; coma; jaundice; severe
anemia
; hypotension; prostration; hyperpyrexia; renal failure etc.
Atypical presentation.
Not responding to
chloroquine
therapy within 48 hours
Recurrence within 2 weeks
Slide52DIAGNOSIS
Involves identification of malaria parasite or its antigens/products in the blood of the patient
The efficacy of the diagnosis is subject to many factors
The different forms of the four malaria species;
The different stages of
erythrocytic
schizogony
;
The
endemicity
of different species;
The inter-relation between the levels of transmission, immunity,
parasitemia
, and the symptom
The problems of recurrent malaria, drug resistance, persisting viable or non-viable
parasitemia
etc.
Slide53The diagnosis of malaria is confirmed by blood tests and can be divided into
microscopic
and
non-microscopic
tests.
The microscopic tests involve staining and direct visualization of the parasite under the microscope.
1. Peripheral smear study
2. Quantitative Buffy Coat (QBC) test
Non microscopic
techiques
involves
- Rapid Diagnostic tests , PCR assays ,
Immunofluorescence
for detection of plasmodia , ELISA for malaria antigens , Western blotting etc.
Differential diagnosis
Malaria can be offered as a differential diagnosis for a big list of diseases.
General:
All other causes of fever, migraine, sinusitis, tension headache etc.
Respiratory system:
Pharyngitis
, bronchitis, pneumonia, bronchopneumonia, pleurisy.
Cardiovascular:
Acute myocardial infarction,
cardiogenic
shock, left ventricular failure,
pericarditis
Abdominal:
Hepatitis, liver abscess,
splenitis
,
splenic
abscess, other causes of
splenomegaly
,
subdiaphragmatic
abscess, acute abdomen,
cholecystitis
,
cholangitis
, gastroenteritis,
amebiasis
, appendicitis, etc.
Central nervous system:
Acute encephalitis, meningitis, intra-cranial space occupying lesions, stroke, metabolic encephalopathy etc.
Psychiatry:
Acute
confusional
states, acute psychosis, mood disorders
Renal:
Acute nephritis,
nephrotic
syndrome, acute renal failure
Haematological:
All other causes of
anemia
; blood
dyscrasias
,
hemoglobinopathies
,
hemolytic
anemias
, intra vascular
hemolysis
, bleeding diathesis, DIC etc.
Slide55TREATMENT
History of treatment
In the ancient times, limb blood-letting, emesis, amputation and skull operations were tried in the treatment of malarial
fever
Artemisinin
:
from the
herb
Artemisia
annua
(sweet wormwood
)
cinchona
bark :
more than 350
years
Many drugs were developed to protect the troops from malaria, particularly during World War II.
Chloroquine
,
Primaquine
,
Proguanil
,
amodiaquine
and
Sulfadoxine
/
Pyrimethamine
were all developed during this time
.
Malarone
:
In 1998 a new drug combination was released in Australia called
Malarone
. This is a combination of
proguanil
and
atovaquone
.
Atovaquone
became available 1992 and was used with success for the treatment of
Pneumocystis
carrinii
. The synergistic combination with
proguanil
is found to be an effective
antimalarial
treatment.
Slide56ANTIMALARIALS -
Anti malarial drugs can be classified according to anti malarial activity and
structure
1. According to anti malarial activity:
Tissue
schizonticides
for causal prophylaxis
: These drugs act on the primary tissue forms of the plasmodia which after growth within the liver, initiate the
erythrocytic
stage. By blocking this stage, further development of the infection can be theoretically prevented.
Pyrimethamine
and
Primaquine
have this activity. However since it is impossible to predict the infection before clinical symptoms begin, this mode of therapy is more theoretical than practical.
Tissue
schizonticides
for preventing relapse
: These drugs act on the
hypnozoites
of P.
vivax
and P.
ovale
in the liver that cause relapse of symptoms on reactivation.
Primaquine
is the prototype drug;
pyrimethamine
. . also
has such activity.
Slide57Blood
schizonticides
: These drugs act on the blood forms of the parasite and thereby terminate clinical attacks of malaria. These are the most important drugs in anti malarial chemotherapy. These include
chloroquine
, quinine,
mefloquine
,
halofantrine
,
pyrimethamine
,
sulfadoxine
,
sulfones
,
tetracyclines
etc.
Gametocytocides
:
These drugs destroy the sexual forms of the parasite in the blood and thereby prevent transmission of the infection to the mosquito.
Chloroquine
and quinine have
gametocytocidal
activity against P.
vivax
and P.
malariae
, but not against P.
falciparum
.
Primaquine
has
gametocytocidal
activity against all plasmodia, including P.
falciparum
.
Sporontocides
:
These drugs prevent the development of
oocysts
in the mosquito and thus ablate the transmission.
Primaquine
and
chloroguanide
have this action.
Thus in effect, treatment of malaria would include a blood
schizonticide
, a
gametocytocide
and a tissue
schizonticide
(in case of
P.
vivax
and
P.
ovale
). A combination of
chloroquine
and
primaquine
is thus needed in ALL cases of malaria.
Slide58Slide59Slide60Slide61Other Drugs for Chemotherapy of Malaria
Clindamycin
:
It acts by inhibiting the protein synthesis by binding to the 50s subunit of
ribosomes
.
Fluoroquinolones
:
Both ciprofloxacin and
norfloxacin
have been found to have anti malarial activity both in vitro and in vivo. However, results are not consistent
.
Azithromycin
:
Azithromycin
is found to have anti malarial activity and has been found to be useful as a causal prophylactic
agent
Pyronaridine
:
Structurally, it resembles
amodiaquine
and has been found to be highly effective against
chloroquine
resistant strains in China.
Piperaquine
:
Its activity is similar to that of
chloroquine
. A combination with
artimisinin
is undergoing studies.
Slide62REFERENCE
Tropical Diseases – Manson Bahr; 19
th
edition ; 1987 ; page 3-47
http://www.malariasite.com/malaria
Slide63THANK YOU
Slide64Slide65