8.Plasmodial Infections (Malaria)

8/3/2019 8.Plasmodial Infections (Malaria)

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PLASMODIAL INFECTIONS (MALARIA)

Phylum: Protozoa

Sub-phylum: Apicomplexa (Sporozoa)

Infective agent:Plasmodium falciparum,

P. malariae,

P. ovale,P. vivax


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INTRODUCTION 1

Is a vector borne disease and the most importantparasitic disease of man.

It is a protozoan infection of RBCs and istransmitted by the blood feeding female

anopheline mosquitoes. Word Malaria comes from the Italians and literally

means bad air (Mal aria) and they believed thatit was caused by a bacteria Bacillus malariae.

It was the French who implicated parasites in thisinfection.

It is caused byPlasmodium sp.


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INTRODUCTION 2

Over 350m people are infected with about 13mdeaths each year mostly African children (90%)

4 species ofPlasmodiuminfect man and thesevaryin their innate virulence depending on the type

of RBCs they infect.

Plasmodium falciparum

P. ovale P. malariae P. vivax

Of these 4 common speciesP. vivax and P.falciparum accounts for 95%of infection.

Malaria is found throughout the tropics andP.

falciparum dominates in Africa.


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Plasmodium vivax

Causes benign tertian malaria with a 48hr cycle.

It covers a large geographic range, more common in

South America, N. Africa, India but rare in South

Saharan Africa.

It tends to have a true relapse from the residual

liver stages.

It infects young RBCs.

Parasite density rarely exceed 50,000 / l of blood.


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Plasmodium ovale

Causes benign tertian malaria with a 48hr cycle.

It covers a narrow geographic range (it is quite rare

out side West Africa and South Pacific islands/regions)

It infects young RBCs


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Plasmodium malariae

Is responsible for quartan malaria with a 72hrcycle.

It covers a narrow geographic range; it is sporadicin distribution but relatively uncommonoutside Africa.

It infects older RBCs.

It is associated with recrudescenceand nephrotic

syndrome with no true relapse. P. vivaxand P. malariaeinfect about 12%or less

RBCs, P. ovaleinfects less than 2%of RBCs.

P. falciparuminfects or parasites up to 3040%.

Parasite density is about 10,000 / l of blood.


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INTRODUCTION 3

Almost all deaths due to malaria and severe diseasecondition are caused by P. falciparum

The other three parasites cause benign malarias and

severe disease condition with these species is un-

usual, however, occasionally patients with such

infection may die from rapture of an enlarged

spleen


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EPIDEMIOLOGY 1

A) THE VECTOR

The main vector is theAnopheles mosquito

Transmission does not occur at temperatures

below16 0C or above 33 0C because the

development of the parasite in the mosquito(sporogony) cannot occur.

These vectors show an important characteristic

vector competence i.e. longevity. This isbecause sporogony requires a weekor more to

occur depending on the temperature.


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EPIDEMIOLOGY 2

Transmission is directly proportional to the

Density of the vectorNumber of times of bites each day and also

The survival of the vector after feeding

Vectors differ in their natural density (abundance)/feeding / resulting behaviors / breeding site

preferences / flight ranges / choice of food (blood)/ vulnerability to environmental conditions and

insecticides. Anopheles gambiae is the most infective vector / are

tough / long lived / naturally occur in high

densities / bite humans frequently.


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EPIDEMIOLOGY 3

B) THE HUMAN HOST

Human behaviour plays a major role in thetransmission of malaria. There is the need forhuman reservoir of gametocytes to transmit theinfection.

In areas of high transmission, infants/young childrenare most susceptible than adults thus parasitedensities tend to be higher in children andgametocytes tend to be detected more frequently

in children. The younger age groups usually represent the main

reservoir group and the main recipients ofinfection.


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EPIDEMIOLOGY 4

Endemicity of infection is defined traditionally in

terms of the spleen or parasite rates (S/P) inchildren between 2- 9 yrs of age.

Hypo-endemic S/P is 010%

Meso-endemic S/P is 1015%

Hyper-endemic S/P is 5070%

Holo-endemic S/P is over 75%

In Holo and Hyper-endemic areas for Plasmodiumfalciparume.g. tropical Africa,people arerepeatedly infected throughout their lives.


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EPIDEMIOLOGY 5

Children who survive infection achieve a state of

premunitionwhere infections cause little or no

problems to host (children).

Premunition is therefore a form of immunity that

develops to control but not to prevent infection.

It is also known that non-immune adults visiting areas

of intense transmission tend to acquirepremunition

more rapidly than children.

Falciparum malaria infections are more severe in

pregnancyparticularly in primigravidae.


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CLINICAL EPIDEMIOLOGY 1

Babies tend to develop severe malaria infrequently, ifthey do, mortality is high.

Factors responsible for infrequent malaria in infantsinclude passive transfer of matenal immunity and

high haemoglobin F contentof infantserythrocytes, which retard parasite development.

Thus there may be lots of inoculation with

sporozoites in the 1st year of life but blood stageinfection may seldomly be severe.

In the 13yr group, falciparummalaria can causesevere anaemia.


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In less intense or unstable transmission, the age

group severely affected extend to the older childrenleading to cerebral malaria

In Holo / Hyper endemic areas - indigenous

adultsnever develop severe malaria unless theymigrate or emigrate because usuallypremunition

prevents parasites from reaching dangerous levels.

Premunition is generally lowin areas where

transmission is infrequent.

Malaria transmission is usually seasonal, it is highin the rainy season; because coincides with theabundance of mosquiotoes.


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Deforestation, population migration and changes in

agricultural practices have increased effect intransmission.

Epidemics are caused by migrations / introduction ofnew vectors or changes in the habits of thevectors

or human hosts. Thus malaria could be imported and this type of

malaria is often mis-diagnosed.

Transmission can also be by blood transfusion /transplantation or through the used of hypodermicneedles which are contaminated by prior use bydrug addicts.


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LIFE CYCLE 1

This is very complex and rich in morphological

details. There are two main stages:a) Human Stages

1) Pre-erythrocytic schizogony

2) Erythrocytic schizogony

3) Erythrocytic gametogonyb) Mosquito Stages

1) Fertilization, meiosis and ookineteformation

2) Formation of oocysts and sporogony Malaria provides an example of stage - development

specificity of invasion.

e.g. sporozoitesliver cells

merozoitesRBCs


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Life cycle of the malaria parasite 2


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LIFE CYCLE 3

A) PRE-ERYTHROCYTIC (Hepatic Phase)

Infection begins when the female anophelesmosquito inoculates plasmodial sporozoites into

the blood stream of man

These small motile sporozoites may be few in theinoculum (815) or can be about 100.

After inoculation, sporozoites enter the circulation

either directly or through the lymph channels andhome to the liver parenchyma cells. This happens

between (within) 45min all sporozoites would have

entered the liver or have been cleared.


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LIFE CYCLE 4

The sporozoites live in the hepatocytes (liver

cells) and begin asexual (schizogonic)reproduction.

Schizogonic phase can last between 5 days (P.

falciparum) to 15 days for (P. malariae)

In P. vivaxand P. ovaleinfections, aproportion

of the intrahepatic parasites do not develop but

go into a state of rest (quiescence) referred to asthe hypnozoites (latent forms) which become

active weeks / months later.


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LIFE CYCLE 4

These quiescent stages (sleeping stages) are

responsible for relapseswhich characterizethose P. vivax/ P. ovaleinfections.

During this asexual phase (schizogony),

multiplication occur producing many

thousands ofmerozoiteswhich are released

from ruptured infected hepatocytes.

This phase is asymptomatic for the human host.

In P. ovale and vivax, hypnozoites are latent forms


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LIFE CYCLE 5 B) ASEXUAL BLOOD STAGE DEVELOPMENT

Erythrocytic schizogonic phaseErythrocytic gametogonic phase

Released merozoites rapidly invade red cells.Attachment of parasite to RBC is facilitated byspecific RBC surface receptors.

e.g. In P. vivax- the duffy blood group antigen Fya orFyb 29, 30 . This antigen is absent in people from

the West Africans region and this explains absenceofP. vivaxinfection among these folks.

Receptors to P. falciparumhave been identified asglycophorins but receptors for P. malariaeand P. ovaleare not known.


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LIFE CYCLE 6

On entry the merozoites undergo severalmorphological changes and development from

Ring Forms (trophozoites) Schizonts Merozoites

In the early stages (less than 12hrs) the ring forms of

all 4 species appear to be identical or similarunder the microscope.

They look like a signet ring or in P. falciparumlike apair of earphones with darkly stained chromatin

in the nucleus, a circular rim of cytoplasm and acentral vacuolethey are motile.

As they growthey consume the contents of theerythrocytes, usually the haemoglobin.


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Ring forms of P.

falciparuminRBCs


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LIFE CYCLE 7

In about 2426hrs of development, P. falciparum

exhibits a high molecular weight strain variant

antigen on the surface of infected RBCs (knob-like

projections) which facilitate attachment to vascular

endothelium.

These RBCs disappear from circulation(sequestration) and attach to the walls of the

vessels (cytoadherence)a process called.

The other 3 species (benign malaria) do not cyto-adhere and all stages of these parasites are found

in the peripheral blood.


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LIFE CYCLE 8

P. vivaxduring growth enlarges the infected RBC

leading to the appearance of red granules (pigments)throughout the RBC called Schffners dots. Theseare also found in P. ovale.

P. malariaeproduces characteristic band forms as

parasites nature.

Infected RBCs rupture releasing merozoites between6 and 36 per RBC.

Asexual life cycle is 48 hrs (tertian malaria) for P.falicparum, P. vivax, P. ovaleand 72hrs (quartanmalaria for P. malariae)


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LIFE CYCLE 9

C) POST ERYTHROCYCTIC STAGE SEXUAL STAGESAND DEVELOPMENT IN THE MOSQUITO

After series of asexual cycles, a sub population ofparasites develops (by gametogomy)into sexualforms (gametocytes), which are long lived andmotile.

The process ofgametogony takes 4 days in P.vivaxinfections and more than 10 days in P.falciparum.

Upon ingestion ofmale and female gametocytesin a blood meal the parasites become activated.

They develop, multiply and fuse to form a zygote.


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Male and Female gametocytes of

P. falciparum

LIFE CYCLE 9


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LIFE CYCLE 9

Within 24hrs the enlarging zygote (ookinete)

becomes motile andpenetrates the walls of the

mosquitos mid gut (stomach) where it encysts

as an oocyst.

The oocyst finally raptures to release myriads of

sporozoites into the coelomic cavity of themosquito.

These sporozoites then migrate to the salivary

glands to await inoculation into the next host

Sporogony and takes between 835 days

depending on ambient temperature / species of

parasites / mosquito.


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HUMAN GENETICS AND MALARIA 1

Genetic polymorphism ofseveral human genes affect

entry / multiplication /survival / development ofmalaria parasites and this determines the outcome

of the infection.

Parasite invasion of RBCs depends on specificsurface moleculeson the RBCs

For P. vivaxduffy antigens

For P. falciparumglycophorin A

Most blackAfrican are duffy antigen negative but

not American blacks.


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Malaria is seldomly found in carriers of the sicklecell trait (Hbs or AS)

P. falciparuminfected RBCs adhere to the walls of

blood vessels via knobs that form as parasitesmature in RBCs (infected)

This sequestration causes the infected orparasitised RBCs to hide in an area of reduced O2

tension which then facilitates sickling / potassium

loss and killing of the parasite.


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Other genetic abnormalities that restrict the growth ofmalaria parasites within RBCs are

G6PDdeficiency and Thalassaemia

(decrease or total absence of a normalglobulin chain )

In this case there is a reduced ability for the RBCs toproduce NADPH via the pentose phosphate shunt,this results in an oxidative stress, which inhibits

parasite growth.

Also certain human leucocyte antigens (HLAS)common in West African also confer protectionagainst severe malaria.

Class 1 antigen HLABW53 and

Class 2 antigen HLADRB1.1302


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PATHOGENESIS AND CLINICAL

MANIFESTATIONS 1

The disease could be uncomplicated or complicated.

The main manifestations of malaria are fever, chillsand anaemia.

The typical malarial paroxysm coincides with thesimultaneous lysisof many RBCs and the releaseof large numbers of merozoites.

How these manifestations are maintained in vivo is

not clear (synchronous parasite development) Only the intra-ertythrocytic (asexual) parasites cause

disease.


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MANIFESTATIONS 2

There are 4 main processes. 1. Feverthe basis remain abscure

2. Anaemia

a. Haemolysis

b. Sequestration of infected RBCs in the spleen. 3. Tissue HypoxiaResulting from anaemia and

alteration in the microcirculation:- pulmonary oedema, renal failure, cerebraldysfunction.

4. Immunologic Events

These include hypoglobulinaemia;antibody mediated splenic sequestration of

platelets, immune complex disease,


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MANIFESTATIONS 3

CLINICALLY

The first symptoms are non-specific and resembleinfluenza and are similar for all 4 species. Non-

specific signs and symptoms include:

Fever (periodic, paroxysms)headaches,muscular ache / vague abdominal discomfort

/ lethargy / lassitude and dysphoria /temperature rise / loss of appetite, chills,hepatomegaly and anaemia, joint pains,sweating.


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MANIFESTATIONS 4

SPECIESSpecific syndromes P. vivaxand P. ovalefever and anaemia

debilitate the patient but is unusual.

P. malariaemortality is rare, it is most oftenassociated with immune complexdisease including an irreversibleglomerulonephritis in children in endemic

areas. P. falciparumcan cause lethal complications

especially in non immune persons andpregnant women.


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MANIFESTATIONS 5

Other complications associcted with severe P.falciparuminfections include:

Cerebral malariaHypoglycemia (especially in pregnantwomen)

Renal failure from acute tubular necrosis

Massive intracellular haemolysis (blackwater fever)

Pulmonary oedema

DIAGNOSIS


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DIAGNOSIS

Microscopic identification of parasites in blood is

the most certain method

Usually thin and thick blood films are prepared

The thick film is examined to detect thepresence of

the parasites

The thin film is examined to identify the species and

to give estimate of the level of parasitaemia

The films are stained in Giemsa stain or

Leishmans, or Fields stains


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ESTIMATION OF NUMBER OF

PARASITES

110 per 100 high power field --- + (1+)

11100 per --- ++ (2+)

110 in every high power field--- +++ (3+)

more than 10 in every high power field-- ++++ (4+)


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PREVENTION AND CONTROL

Avoiding mosquito bites

Use of drugs Prevention of mosquito breeding

Elimination of all adult mosquitoes

Health education Immunization

TREATMENT


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TREATMENT

Available antimalarials are in 3 broad groups

1. Quinoline-related CompoundsQuinines, quinidine, chloroquine, amodiaquine,mefloquine, Halofantrine, primaquine.

2.Antifols

Prymethamine, proguanil, chlorproguanil,trimethoprim

3. Artemisinin Compounds

Artemisinin, artemether, artesunate Of these three groups, theArtemisinin compounds

have the broadest time windowof action on asexualmalaria parasites from medium sized rings to early

shizonts.


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8.Plasmodial Infections (Malaria)

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