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MALARIA Assignment on BCH 514 Clinical Biochemistry

Submitted by. Selma Abdul . Samad. BCH-10-05-02. S3 . MSc.Biochemistry. What is Malaria ??. An infectious tropical Disease caused by the parasite Plasmodium sp. in . humans. The name malaria derived from the Italian .

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MALARIA Assignment on BCH 514 Clinical Biochemistry






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Slide1

MALARIA

Assignment on

BCH 514 Clinical Biochemistry

Submitted by

Selma Abdul

Samad

BCH-10-05-02

S3

MSc.Biochemistry

Slide2

What 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.

Slide3

Geographical 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.

Slide4

Geographical Distribution

Slide5

Slide6

In India ..

Orissa, Chhattisgarh, West Bengal, Jharkhand and Karnataka contribute the most number of cases of malaria in India

Slide7

HISTORY 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.

Slide8

Man 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

Slide9

Different 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

Slide10

Famous 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………………..

Slide11

Scientific 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

Slide12

Time 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

Slide13

Several 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

Slide14

Nobel 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.

Slide15

Julius 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".

Slide16

Etiology

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

Slide17

The Malaria Parasites

Protozoan parasites called Plasmodia

Phylum: Protozoa

Class:

Sporozoa

Genus: Plasmodia

Species : several species, 5 known to affect man

Slide18

Slide19

Slide20

INFECTION

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.

Slide21

The 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.

Slide22

Anopheles 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

Slide23

Other 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

Slide24

LIFE 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

Slide25

 The 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

Slide26

Sporogony 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

Slide27

The 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.

Slide28

When 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)

Slide29

Malaria

oocysts

on stomach of mosquito

Slide30

Schizogony 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.

Slide31

The

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.

Slide32

The 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.

Slide33

The

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.

Slide34

Erythrocytic

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.

Slide35

The 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.

Slide36

The 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”.

Slide37

Slide38

The 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.

Slide39

The

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

.

Slide40

Gametogony

:

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.

Slide41

Slide42

Slide43

Slide44

PATHOLOGY

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.

Slide45

RBC 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

Slide46

GI 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

Slide47

CLINICAL 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.

Slide48

In

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.

Slide49

Atypical 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

Slide50

Acute abdomen

Weakness

Vomiting and diarrhoea

Jaundice

Pallor

Puffiness of lids

Secondary infections

Hepatosplenomegaly

Combinations of the above

Slide51

Clinical 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

Slide52

DIAGNOSIS

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.

Slide53

The 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.

Slide54

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.

Slide55

TREATMENT

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.

Slide56

ANTIMALARIALS -

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.

Slide57

Blood

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.

Slide58

Slide59

Slide60

Slide61

Other 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.

Slide62

REFERENCE

Tropical Diseases – Manson Bahr; 19

th

edition ; 1987 ; page 3-47

http://www.malariasite.com/malaria

Slide63

THANK YOU

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