1. The document discusses the clinical aspects of malaria, including the life cycle and characteristics of the four Plasmodium species that infect humans. 2. It covers the pathophysiology of malaria, including the toxicity of cytokines, sequestration of infected red blood cells, and rosetting. It also discusses the clinical manifestations of malaria like cerebral malaria, anemia, and hypoglycemia. 3. The diagnosis, treatment, complications and prevention of malaria are summarized along with the features of uncomplicated and severe malaria infections.

1. Clinical Aspects of Malaria
HUMAN MALARIA PARASITES
REVISION OF LIFE CYCLE
• Characteristic of Plasmodium Species Infecting Humans.
THE INFECTION
• Susceptibility for infection.
PATHOPHYSIOLOGY
• Toxicity cytokines:
• Sequestration
• Rosetting:
• Pathogenesis of Coma
• Anaemia
• Blackwater fever:
• The spleen
• Hypoglycemia

2. PATHOLOGY CLINICAL FEATURES
• Brain • Severity and immune status
• Heart and lungs • Incubation period
• Liver and spleen • Uncomplicated Malaria: (UCM)
• Kidneys • Cerebral Malaria:
• Alimentary Tract • Relapse & recrudescence.
• Bone marrow: • Severe Malaria:
• Placenta: • Anaemia
( Optional reading) • Acute renal Failure
• Metabolic Acidosis.
• Black water fever.
• Acute Pulmonary oedema.
• Algid Malaria (Hypotension).
• Hypoglycemia
• Malaria In Children
• Malaria in Pregnancy

3. DIAGNOSIS
• Blood smear
• Other Techniques
CHRONIC COMPLICATIONS OF MALARIA
• Hyperactive Malarial splenomegally
• Quartan Malarial Nephropathy
• Burkitt’s Lymphoma
TREATMENT
ANTIMALARIAL DRUGS
CHOICE OF DRUGS

4. Clinical Aspects of Malaria
• Over 500 million people each year, debilitating attacks
• About 1 - 3 millions are fatal.
• Up to 2.7 million deaths occur each year ( WHO,1996)
The disease in humans
Caused by
• Direct effects of red cells invasion and
• Destruction By:
1. The asexual parasite and
2. The host’s reaction.

5. The Life Cycle of Malaria Parasite in the Mosquito and in
the Human host

6. Characteristic of Plasmodium Species Infecting Humans.
P. falciparum P. Vivax P. ovale P .malariae
Exo-erythrocytic 5.5 8 9 15
hepatic phase of
development (days)
Erythrocytic cycle 2 2 2 3
(days)
Hypnozoites (relapses) No Yes Yes No
No of merozoites per 30000 10000 15000 2000
hepatic schizont
Erythrocyte Young RBCs but Reticulo- Reticulo- Old RBCs
preference can invade all ages cytes cytes
Maximum duration of 2 4 4 40
untreated infection
(years)

7. Susceptibility for infection
Universal, except in persons with Certain genetic Traits
Glucose-6-Phosphate Dehydrogenase Deficiency
Trait:
• Offers protection against P. falciparum infection
Duffy blood factor [ Fya or Fyb ] Go to slide 33
• Serve as a site for attachment or penetration on the
surface of RBCs for P. vivax.
• Negative Duffy factor offers protection against P. Vivax
(West Africa) .

8. Sickle-cell anaemia trait:
• Abnormal haemoglobin. Go to slide 34
• P. falciparum schizonts have difficulty in utilizing
this haemoglobin
Other haemoglobins
• Thalassemia haemoglobin and Haemoglobin E. (P. vivax)
• Hb F do not support parasitic growth, protects against
all human plasmodia

9. Melanesian ovalocytic erythrocytes
Resist invasion by malaria parasite .
Melanesia This is a group of several hundred islands east of New
Guinea. The largest island is Guadalcanal.
Certain human leucocyte antigens (HLAs)
ATP deficiency
Nutritional deficiencies
Go to slide 36

10. Virulence factors
1. Multiplication capacity.
2. Cytoadherence.
3. Rosetting ability.
4. The potential to induce cytokine release.
5. Antigenicity.
6. Antimalarial drug resistance

11. PATHOPHYSIOLOGY
Results from
 Destruction of erythrocytes.
• Liberation of parasites and erythrocytes material
• Host reaction to those events.
 P. falciparum malaria-infected erythrocytes
• Sequester in the micro-circulation of vital organs,
• Interfering with
• Microcirculatory flow
• Host tissues metabolism.

14. Toxicity Cytokines
• Malaria parasites induce release of cytokines.
• Cells of macrophage-monocyte series, and possibly
endothelium are stimulated to release cytokines.
• Initially TNF and IL-1 are produced and in turn induce
release of other pro-inflammatory cytokines including
IL-6 then IL-8.
• Cytokines ( mainly TNF) are responsible for many of
the symptoms and sign of the infection.
• Cytokines may be an important mediator of parasite
killing by activating leucocytes.

16. Sequestration
 Adherence of erythrocytes containing mature
forms of P. falciparum to microvascular endothelium
(Cytoadherence) and disappear from peripheral circulation
 Occurs predominantly in the veinules of vital organs.
 Enhanced by cytokines ( adhesion on parasitized RCBs [70%]
and ligand on endothelial cells

19. Rosetting
• Erythrocytes containing mature parasites also
adhere to uninfected erythrocytes.
• This process leads to the formation of rosettes.

20. Pathogenesis of Coma in cerebral
malaria
Is not known, may be due to:
• Increase in cerebral anaerobic glycolysis (with blood
flow of low arterial oxygen content)
• Increased cerebral metabolic rate for lactate.
• Increased CSF concentration of lactate.
• Presumably the metabolic milieu created adjacent to
the sequestrated and highly metabolic parasites
interferes with neurotransmission.
• Cytokines increase production of nitric acid, a potent
inhibitor of neurotransmission

21. Usually normocytic
Anaemia
The pathogenesis is multifactorial and complex:
1. Obligatory destruction of parasitized red cells.(a)
2. Accelerated destruction of parasitized red cells.
(immunopathological mechanisms)(b)
Parasite antigens, or immune complexes containing parasite
antigens, may bind to parasitized red and accelerate their
clearance by the cells of macrophage
3. Autoantibodies produced against normal red cells, again
accelerate their removal.(c)
4. TNF released in response to infection, inhibits red
blood cells development from bone marrow stem cells. (d)

23. Blackwater Fever
A condition in which there is massive intravascular
haemolysis with passage of Coca-cola-coloured urine.

24. The spleen
• Considerable splenic enlargement with increased
capacity to clear red cells from the circulation both by:
- Fc receptor-mediated ( immune ) mechanism.
- Recognition of reduced deformability (filtration).
• Plays a central role in limiting the expansion of
malaria by removing parasitized erythrocytes
Plasmodium
falciparum:
enlarged, heavily
pigmented spleen
is seen in gross
section.

25. Hypoglycemia
Pathophysiological etiology
1. Increased peripheral requirement for glucose upon
anaerobic glycolysis.
2. Increased metabolic demand of the febrile illness.
3. The obligatory demands of the parasite, which use
glucose as their major fuel.
4. Failure of hepatic gluconeogenesis and glycogenolysis.
5. Quinine-induced (hyperinsulinaemic), occur 24 hours
after treatment.

26. CLINICAL FEATURES OF MALARIA
The severity and course of an attack of
malaria depends on:
1. Species and strain of parasite ( geographical
origin).
2. Age of host.
3. Genetic constitution.
4. State of immunity.
5. General health and nutritional status of pt.
6. Chemoprophylaxis or chemotherapy used.

27. Depend on the previous immune status of the host.
 Intense P. falciparum malaria transmission
 Asymptomatic parasitaemia in adults ( premunition )
 No severe malaria in this age group.
 Severe malaria in the first year of life, decline with increasing
age.
 Severe anaemia is the most common presentation of severe
falciparum malaria in infancy.
 Spleen rates will be high(>50%) in children between 2 - 9 years.
 With unstable transmission
 The age distribution of severe malaria shifts upwards, Older
children as well,
 Cerebral malaria is most prominent.
 Spleen rates in children is lower than 50%.
 With lower or sporadic pattern of transmission, and non-immune
travelers to endemic areas, symptomatic disease is seen in all ages.

29. Incubation period
The prepatent period
(time from sporozoite inoculation until
demonstrating parasites in blood film).
The incubation period Go to slide 32
(time from sporozoite inoculation to fever).

30. Uncomplicated Malaria: (UCM)
 The clinical features of UCM are common to all four species.
 First symptoms are non-specific, resemble influenza.
1. Lack of sense of well-being.
2. Headache.
3. Fatigue.
4. Abdominal discomfort.
5. Muscle aches followed by fever.
 The temperature rises erratically at first, with shivering, mild
chills, worsening headache and malaise, and loss of appetite.
 If the infection is left untreated, the fever:-
 in P. vivax and P. ovale regularize to a 2-day cycle (tertian)
 P. malariae fever spikes occur 3 days(quartan) pattern.
 P. falciparum remains erratic for longer, and may never
regularize to a pattern (Quotidian).

31. In a true paroxysm
1. The temperature rises steeply to exceed 39 C.
2. Intense headache and muscular discomfort.
3. The patient feels cold, clutches at blankets, and curls up
shivering, uncommunicative (the chill).
4. There is vasoconstriction, within minutes the limbs begin to
shake and the teeth chatter.
5. The temperature climbs rapidly to a peak ( 39 -41.5 C).
6. The rigors lasts 10 - 30 minutes and may be up to 90 minutes.
7. By the end of rigors, there is vasodilatation , the skin feels hot,
then a profuse sweating breaks out.
8. The blood pressure is relatively low & may be symptoms of
orthostatic hypotension.
9. The patient feels exhausted and may sleep.
10. Defervescence takes 4 - 8 hours

32.  As the infection continue the spleen and liver enlarge
and anaemia develops, and patient loss weight.
 If no treatment is given the natural infection stabilizes
for several weeks or months then gradually resolves.
 Mild abdominal pain is common in malaria,
constipation or diarrhea may occur
 In the tropics malaria is so common that it must be
excluded in any febrile patient.

33. Thank You

34. Go back to slide 27

35.  Low activity of this enzyme results in
subnormal concentration of reduced
glutathione in red cells and also in the
limitation of the hexose monophosphate
shunt pathway ( e.g. production of
essential ribose phosphate ). P. falciparum
use this pathway in their metabolism.
Go back to slide 7

36. Haemoglobin Molecules is tetramer:
Adult normal HbA = 2 α chains + 2 β chains
HbS : there is amino acid substitution ( valine for glutathione at
position 17) in the β chain
Heterozygotes for HbS have one normal and one defective β gene &
are said to have sickle triat and are designated AS, their RBCs
contain mixture of HbA and HbS and function fairly normal
RBCs of homozygos (SS) contain mainly HbS (2 abnormal β genes),
at low Oxygen tension their cell form abnormal shape (sickle)
Next

37. Go Back to slide 8
Figure 2. Schematic representation of the effect of the sickle cell
hemoglobin gene on survival in endemic malarial areas.
People with normal hemoglobin (left of the diagram) are susceptible to
death from malaria.
People with sickle cell disease (right of the diagram) are susceptible to
death from the complications of sickle cell disease.
People with sickle cell trait, who have one gene for hemoglobin
A and one gene for hemoglobin S, have a greater chance of
surviving malaria and do not suffer adverse consequences from
the hemoglobin S gene.

38. Table 1: Red Cell Defenses Against Malaria
Cell Component Alteration Global Distribution
Membrane Duffy antigen null Africa
Melanesian
Melanesia
Elliptocytosis
Hemoglobin Hemoglobin S Africa, Middle East, India
Hemoglobin C Africa
Hemoglobin E S.E. Asia
ß-thalassemia Africa, Mediterranean,
India, S.E. Asia, Melanesia
-thalassemia Africa, India, S.E. Asia
Africa, Mediterranean,
Red cell enzymes G-6-PD deficiency
India, S.E. Asia
Go back to slide 9