Malaria is endemic in Kenya, where it is a major cause of morbidity and mortality, accounting for 30-50% of outpatient visits and 20% of deaths in children under 5. The life cycle of Plasmodium involves transmission between humans and mosquitoes. In humans, the parasite infects liver cells and red blood cells, destroying RBCs and causing symptoms. Sequestration of P. falciparum-infected RBCs in organs can cause complications like coma, renal failure, pulmonary edema, anemia and more. Diagnosis and management of malaria aims to reduce this significant disease burden.

1. 3/27/2015 1
Presenter;
Ngumi M. Gideon
MBChB IV
©KENYA
Facilitator
Dr. Farida Kaittany
Senior Lecturer,
Consultant Physician.

2. 
 Objectives
 Epidemiology
 Life cycle
 Pathophysiology & Pathogenesis
 Clinical features
 Complications & Severe malaria
 Diagnosis
 Management & prophylaxis
Outline
3/27/2015 2

3. 
 To understand the epidemiology of malaria in Kenya
 To understand the life cycle of the plasmodium and
specific pathophysiological correlates.
 To understand the pathogenesis and complications
of malaria
 To understand the clinical features, management and
diagnosis of malaria
 Diagnosis and management of severe malaria
3/27/2015 3
Objectives

4. 
 Malaria is endemic in 109 countries and is found
throughout the tropics.
 Malaria is the leading cause of morbidity and mortality in
Kenya.
 30 million out of 42 million Kenyans are at risk of malaria.
 It accounts for 30 – 50% of all outpatient attendance and
20% of all admissions to health facilities.
 Malaria is estimated to cause 20% of all deaths in children
under 5. (MOH 2006)
KEMRI Kenya malaria factsheet (www.kemri.org)
Epidemiology
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5. 
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6. 
 High malaria risk areas: Lakeside, coastal, highland and
arid areas
 Low malaria risk areas: Highlands within central
province
 Modes of transmission
-Vector bite
-Blood transfusion
-Organ transplant
-Intravenous drug use
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7. 
 Human malaria can be caused by four species of the
genus Plasmodium: P. falciparum, P. vivax, P. ovale, P.
malariae. Ocassionally other species of malaria
usually found in primates can affect man.
 Malaria is transmitted by the bite of female
anopheline mosquitoes. The parasite undergoes a
temperature-dependent cycle of development in the
gut of the insect, and its geographical range therefore
depends on the presence of the appropriate
mosquito species and on adequate temperature
Life cycle
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8. 
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9. 
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10. 
 Infection with human malaria begins when the
feeding female anopheline mosquito inoculates
plasmodial sporozoites at the time of feeding.
 After injection, they enter the circulation, either
directly or via lymph channels (approximately 20%),
and rapidly target the hepatic parenchymal cells.
 Within 45 min of the bite, all sporozoites have either
entered the hepatocytes or have been cleared.
Pre-erythrocytic development
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11. 
 Each sporozoite bores into the hepatocyte and there
begins a phase of asexual reproduction. This stage lasts
on average between 5.5 (P. falciparum) and 15 days (P.
malariae) before the hepatic schizont ruptures to release
merozoites into the bloodstream.
 In some instances, the primary incubation period can be
much longer. In P. vivax and P. ovale infections a
proportion of the intrahepatic parasites do not develop,
but instead rest inert as sleeping forms or ‘hypnozoites’,
to awaken weeks or months later, and cause the relapses
which characterize infections with these two species
Pre-erythrocytic
development..CNTD
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12. 
 The merozoites released by hepatocytes rapidly
infect RBCs. The attachment of the merozoite to the
red cell is mediated by the attachment of one or more
of a family of erythrocyte binding proteins.
 In P. vivax this is related to the Duffy blood group
antigen.
 For P. falciparum the merozoite protein EBA 175
binds to red cell membrane sialoglycoprotein
glycophorin A
Asexual blood-stage development
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13. 
 As they grow, they increase in size logarithmically and
consume the erythrocyte’s haemoglobin. With this increase
in size, P. falciparum-infected erythrocytes become spherical
and less deformable, whereas P. vivax enlarges the infected
red cells, which become more deformable.
 Proteolysis of haemoglobin within the digestive vacuole
releases amino acids which are taken up and utilized by the
growing parasite for protein synthesis, but the liberated
haem poses a problem. When haem is freed from its protein
scaffold, it oxidizes to the toxic ferric form. Intraparasitic
toxicity is avoided by spontaneous dimerization to an inert
crystalline substance, haemozoin
Asexual blood-stage development
...CNTD
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14.  At approximately 12–14 h of development, P. falciparum
parasites begin to exhibit a high molecular weight strain-
specific variant antigen, Plasmodium falciparum erythrocyte
membrane protein 1 (PfEMP1) on the exterior surface of the
infected red cell which mediates attachment of the infected
erythrocyte to vascular endothelium.
 This is associated with knob-like projections from the
erythrocyte membrane. Expression increases towards the
middle of the cycle (24 h). These ‘knobby’ or K+ red cells
progressively disappear from the circulation by attachment or
‘cytoadherence’ to the walls of venules and capillaries in the
vital organs.
 This process is called ‘sequestration’. The other three ‘benign’
human malarias do not cytoadhere in systemic blood vessels
and all stages of development circulate in the bloodstream
Asexual blood-stage development
...CNTD
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15. 
 Inside the red cells the parasites again multiply,
changing from merozoite, to trophozoite, to schizont,
and finally appearing as 8-24 new merozoites.
 The erythrocyte ruptures, releasing the merozoites to
infect further cells.
 Each cycle of this process, which is called erythrocytic
schizogony, takes about 48 hours in P. falciparum, P.
vivax and P. ovale, and about 72 hours in P. malariae. P.
vivax and P. ovale mainly attack reticulocytes and
young erythrocytes, while P. malariae tends to attack
older cells; P. falciparum will parasitize any stage of
erythrocyte.
Asexual blood-stage development
...CNTD
3/27/2015 15

16. 
 After a series of asexual cycles ( P. falciparum) or immediately
after release from the liver ( P. vivax, P. ovale, P. malariae, P.
knowlesi), some of the parasites develop into morphologically
distinct, longer-lived sexual forms ( gametocytes) that can
transmit malaria.
 After being ingested in the blood meal of a biting female
anopheline mosquito, the male and female gametocytes form a
zygote in the insect’s midgut. This zygote matures into an
ookinete, which penetrates and encysts in the mosquito’s gut
wall.
 The resulting oocyst expands by asexual division until it bursts
to liberate myriad motile sporozoites, which then migrate in
the hemolymph to the salivary gland of the mosquito to await
inoculation into another human at the next feeding.
Sexual stages and development in the mosquito
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17. 3/27/2015 17

18. 
 The pathophysiology of malaria results from
destruction of erythrocytes, the liberation of parasite
and erythrocyte material into the circulation, and the
host reaction to these events.
 P. falciparum malaria-infected erythrocytes
sequester in the microcirculation of vital organs,
interfering with microcirculatory flow and host
tissue metabolism.
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19. 
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20. 
 Erythrocytes containing mature forms of P. falciparum
adhere to microvascular endothelium
(‘cytoadherence’) and thus disappear from the
circulation. This process is known as sequestration
 Once infected red cells adhere, they do not enter the
circulation again, remaining stuck until they rupture
at merogony.
 Cytoadherence and the related phenomena of
rosetting and autoagglutination lead to
microcirculatory obstruction in falciparum malaria.
Cytoadherence &
sequestration
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21. 
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22. 
Red cell ligand Vascular endothelial
receptors
Location of the
vascular endothelial
receptors
Plasmodium
falciparum erythrocyte
membrane protein 1
(PfEMP1)
CD36. Most organs
Intercellular adhesion
molecule 1 (ICAM 1)
Brain
Chondroitin sulphate
A (CSA)
Placenta
Vascular endothelial
ligands
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23. 
 As Plasmodium vivax matures inside the erythrocyte, the
cell enlarges and becomes more deformable.
 Plasmodium falciparum does exactly the opposite; the
normally flexible biconcave disc becomes progressively
more spherical and rigid.
 The reduction in deformability results from reduced
membrane fluidity, increasing sphericity, and the
enlarging and relatively rigid intraerythrocytic parasite.
Infected red cells are less filterable than uninfected cells,
and readily removed by the spleen.
 Indeed it has been argued that sequestration is an
adaptive response to escape splenic filtration
Red cell deformability
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24. 
 There is evidence of a mild generalized increase in
systemic vascular permeability in severe malaria.
 Focal perivascular and intraparenchymal oedema is seen
in the brain in 70% of fatal cases.
 In the past, it was suggested that cerebral malaria resulted
from a marked generalized increase in cerebral capillary
permeability which led to brain swelling, coma and death,
but the imaging studies conducted to date indicate that,
although there may be some increases in brain water, as
would be expected given the widespread venular and
capillary obstruction, the majority of adults and children
with cerebral malaria do not have significant cerebral
oedema
Permeability
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25. 
 Coma in severe malaria is called cerebral malaria.
Although several factors may contribute to impaired
consciousness in severe malaria (seizures,
hypoglycaemia), there is a syndrome of diffuse but
reversible encephalopathy which is characteristic of
malaria, and is not seen in other infections.
 The cause of coma is not known. There is undoubtedly an
increase in cerebral anaerobic glycolysis with cerebral
blood flows that are inappropriately low for the arterial
oxygen content, increased cerebral metabolic rates for
lactate, and increased CSF concentrations of lactate, but
these changes, which reflect impaired perfusion, do not
provide sufficient explanation for coma.
Pathogenesis of coma
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26. 
 There is renal cortical vasoconstriction and consequent
hypoperfusion in severe falciparum malaria. In patients
with acute renal failure (ARF) renal vascular resistance is
increased.
 The renal injury in severe malaria results from acute
tubular necrosis.
 Acute tubular necrosis presumably results from renal
microvascular obstruction and cellular injury consequent
upon sequestration in the kidney and the filtration of
nephrotoxins such as free haemoglobin, myoglobin and
other cellular material
Renal failure
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27. 
 Pulmonary oedema in malaria results from a sudden
increase in pulmonary capillary permeability that is
not reflected in other vascular beds.
 Whereas acute renal failure, severe metabolic
acidosis, and coma are confined mainly to
falciparum malaria, acute pulmonary oedema may
also occur in vivax malaria.
 The cause of this increase in pulmonary capillary
permeability is not known
Pulmonary oedema
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28. 
 -Anemia in malaria is multifactorial.
1. Haemolysis of RBC infected by the protozoa
2. Accelerated destruction of non-parasitised red cells
(major contributor in anemia of severe malaria)
3. Bone marrow dysfunction that can persist for weeks
4. Shortened red cell survival
5. Increased splenic clearance
6. Massive gastrointestinal haemorrhage can also contribute
to the anemia of malaria.
7. Drug caused haemolysis.
3/27/2015 28
Anemia

29. 
Causes of anaemia in malaria infection
Haemolysis of infected red cells
Haemolysis of non-infected red cells (blackwater fever)
Dyserythropoiesis
Splenomegaly and sequestration
Folate depletion
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30. 
 In acute malaria, coagulation cascade activity is
accelerated with accelerated fibrinogen turnover,
consumption of antithrombin III, reduced factor XIII,
and increased concentrations of fibrin degradation
products.
 Thrombocytopenia is common to all the four human
malarias and is caused by increased splenic
clearance.
Coagulopathy and
thrombocytopenia
3/27/2015 30

31. 
 It is a poorly understood condition in which there is
massive intravascular haemolysis and the passage of
‘Coca-Cola’-coloured urine.
 It is related to use of quinine.
 G6PD-deficient red cells are particularly susceptible to
oxidant stress as they are unable to synthesize adequate
quantities of NADPH through the pentose shunt.
 This leads to low intraerythrocytic levels of reduced
glutathione, and both alterations in the erythrocyte
membrane and increased susceptibility to organic
peroxides
Blackwater fever
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32. 
 There is considerable splenic enlargement in malaria,
mainly as a result of cellular multiplication and
structural change, and an increased capacity to clear
red cells from the circulation both by Fc receptor-
mediated (immune) mechanisms and by recognition
of reduced deformability (filtration).
 There is considerable accumulation of parasitized
erythrocytes.
The spleen
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33. 
 Abdominal pain may be prominent in acute malaria.
 Minor stress ulceration of the stomach and
duodenum is common in severe malaria.
 Gut permeability is increased,and this may be
associated with reduced local defences against
bacterial toxins, or even whole bacteria in severe
disease.
Gastrointestinal
dysfunction
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34. 
 Jaundice is common in adults with severe malaria,
and there is other evidence of hepatic dysfunction,
with reduced clotting factor synthesis, reduced
metabolic clearance of the antimalarial drugs, and a
failure of gluconeogenesis which contributes to lactic
acidosis and hypoglycaemia.
 Jaundice in malaria appears to have haemolytic,
hepatic, and cholestatic components.
Liver dysfunction
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35. 
 Acidosis is a major cause of death in severe
falciparum malaria, both in adults and children.
 This has been considered to be mainly a lactic
acidosis, although ketoacidosis may predominate in
children, and the acidosis of renal failure is common
in adults.
 Lactic acidosis results from several discrete
processes: the tissue anaerobic glycolysis consequent
upon microvascular obstruction; a failure of hepatic
and renal lactate clearance; and the production of
lactate by the parasite.
Acidosis
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36. 
 It is an important manifestation of severe malaria.
 An increased peripheral requirement for glucose
consequent upon anaerobic glycolysis, the increased
metabolic demands of the febrile illness, and the
obligatory demands of the parasites, which use glucose as
their major fuel (all of which increase demand); and a
failure of hepatic gluconeogenesis and glycogenolysis
(reduced supply).
 The combination of impaired gluconeogenesis, limited
glycogen stores, and greatly increased demand results in
hypoglycaemia in 20–30% of children with severe malaria.
Hypoglycaemia
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37. 
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WHO DEFINITION OF
SEVERE MALARIA
 Cerebral malaria
 Severe anaemia
 Renal failure
 Pulmonary oedema or
adult respiratory distress
syndrome
 Hypoglycaemia
 Circulatory collapse or
shock
 Prostration
 Hyperparasitaemia
 Spontaneous bleeding from
gums, nose, gastrointestinal
tract, etc. and/or substantial
laboratory evidence of DIC.
 Repeated generalized
convulsions
 Acidaemia
 Macroscopic
haemoglobinuria
 Impairment of
consciousness less marked
than unrousable coma

38. 
3/27/2015 38

39. 3/27/2015 39

40. 
 The normal incubation period is 10-21 days, but can
be longer. The most common symptom is fever,
although malaria may present initially with general
malaise, headache, vomiting, or diarrhoea.
 At first the fever may be continual or erratic: the
classical tertian or quartan fever only appears after
some days. The temperature often reaches 41°C, and
is accompanied by rigors and drenching sweats
3/27/2015 40

41. 
 The illness is relatively mild.
 Anaemia develops slowly, and there may be tender
hepatosplenomegaly.
 Spontaneous recovery usually occurs within 2-6
weeks, but hypnozoites in the liver can cause
relapses for many years after infection.
 Repeated infections often cause chronic ill health due
to anaemia and hyperreactive splenomegaly.
3/27/2015 41
P. vivax or P. ovale
infection

42. 
 This also causes a relatively mild illness, but tends to
run a more chronic course.
 Parasitaemia may persist for years, with or without
symptoms.
 In children, P. malariae infection is associated with
glomerulonephritis and nephrotic syndrome.
3/27/2015 42
P. malariae infection

43. 
 This causes, in many cases, a self-limiting illness similar
to the other types of malaria, although the paroxysms of
fever are usually less marked.
 Patients can deteriorate rapidly, and children in particular
progress from reasonable health to coma and death
within hours.
 A high parasitaemia (> 1% of red cells infected) is an
indicator of severe disease, although patients with
apparently low parasite levels may also develop
complications. Cerebral malaria is marked by diminished
consciousness, confusion, and convulsions, often
progressing to coma and death.
3/27/2015 43
P. falciparum infection

44. 
1. Extremes of age.
2. Pregnancy, especially in primigravidae and in 2nd half of
pregnancy.
3. Immunosuppressed - patients on steroids, anti-cancer
drugs, immunosuppressant drugs.
4. Immunocompromised - patients with advanced
tuberculosis and cancers.
5. Splenectomy.
6. Lack of previous exposure to malaria (non-immune) or
lapsed immunity
7. Pre-existing organ failure.
3/27/2015 44
Predisposing factors for
complications of P. falciparum
malaria:

45. 
 This is seen in older children and adults in areas
where malaria is hyperendemic.
 It is associated with an exaggerated immune
response to repeated malaria infections, and is
characterized by anaemia, massive splenomegaly,
and elevated IgM levels.
 Malaria parasites are scanty or absent.
 TSS usually responds to prolonged treatment with
prophylactic antimalarial drugs
3/27/2015 45
Hyperreactive malarial
splenomegaly (tropical
splenomegaly syndrome, TSS)

46.  There is gross splenomegaly with normal
architecture, and lymphocytic infiltration of the
hepatic sinusoids with Kupffer cell hyperplasia.
 The massively enlarged spleen leads to
hypersplenism with anaemia, leucopenia and
thrombocytopenia.
 There is a polyclonal hypergammaglobulinaemia
with high serum concentrations of IgM. High titres
of malaria antibodies and a variety of autoantibodies
(antinuclear factor, rheumatoid factor) are usually
present.
HMS/TSS
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47. 
3/27/2015 47

48. 
INVESTIGATION
1.Microscopy:
 Thin and thick blood smears for MPS
 Thick films: Parasite ID & Quantifcn; Monitor Rx
 Thin films: Species Identification
 Sensitivity: 86-96%
 Quantification: Ring form count/200WBCs or parasite/μL
(assume WBC count of 8000/μL)
Plus system:
+ represents 1-10/100 thick blood films
++ represents 11-100/100 thick blood films
+++ represents 1-10 per single thick blood film
++++ > 10 parasites per single thick blood film

50. 
slides

51. 
contd

55. 
INVESTIGATION
CONT’D
2.QBC - Quantitative Buffy Coat
3.PCR – Polymerase chain reaction
4.RDT – Rapid Diagnostic Test
 Immunochromatographic
 Detect parasite antigen Eg pLDH, HRP
5.Clinical chemistry
6.Roentography
7.Radiological imaging.
8.General investigations

56. 
TREATMENT
Uncomplicated malaria:
1st line: ACT (AL)
 20mg Artemether + 120mg Lumefantrine
 6 dose regime over 3/7
 1st dose DOT
 Take AL prefferably with a meal
Supportive Mx
 Fever :hyperpyrexia (T>39.5°C)-paracetamol or
Ibuprofen + mechanical methods.
 Adequate fluids and nutrition.

57. 

58. 
TREATMENT CONT’D
Treatment failure
 Deterioration or persistence of Sx 3-14/7 after initiation of
Rx
 Get Hx of :Compliance, vomiting of meds
 Mx:
 Repeat microscopy
 2nd line Rx
 Repeat full 1st line dose in Non compliance
 Investigate for other DDx

59. 
TREATMENT CONT’D
 2nd line Rx
 Oral quinine 30mg/kg in 3 dvd doses x7/7 followed by
fansidar 3 tabs single dose

60. 
alternative
► Mefloquine 25mg/kg in 2 doses 8hrs apart
► Malarone(atovaquone 250mg+proguanil 100mg 4
tabs daily for 3 days)
► Eradication for p.vivax and p.ovale-oral primaquine
15mg daily for 14 days.

61. 

62. 
 Artesunate (2.4 mg/kg stat IV followed by 2.4 mg/kg at
12 and 24 h and then daily if necessary)
or, if unavailable, one of the following:
 Artemether (3.2 mg/kg stat IM followed by 1.6 mg/kg
qd)
or
 Quinine dihydrochloride (20 mg of salt/kg infused over 4
h, followed by 10 mg of salt/kg infused over 2–8 h q8h)
or
 Quinidine (10 mg of base/kg infused over 1–2 h, followed
by 1.2 mg of base/kg per hour with electrocardiographic
monitoring)
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Severe Malaria Tx

63. 
Mx SPECIFIC
CLINICAL Sx
Cerebral malaria
 Clinical assessment:
 LOC using GCS
 Severe anaemia
 Resp. Distress
 Hydration status
 Renal insufficiency
 DIC
 Labs:RBS, CSF, UECs etc

64. 
Acidosis
Fluid replacement
 Normal saline bolus 20 ml/kg
 Maintenance Dextrose/saline 4-6ml/kg/hr
 Albumin
Close monitoring
 Check Hb
 Change fluid regimen
Bicarbonate
 Not indicated unless blood gas shows HCO3 <10 mmol
with no response to fluids

65. 
Respiratory Distress
Treat the underlying cause
 Antimalarials
 Correct hypoglycaemia
 Stop seizures
Think about the mechanisms
 hypovolemia
 anaemia
 impaired perfusion
 Salicylates
 Pulmonary oedema

66. 
Seizures
 Diazepam - IV 0.3 mg/Kg or PR 0.5 mg/Kg
 Paraldehyde - IM 0.4 ml/Kg or PR 0.8ml/
 Lorazepam – IV
 Midazolam - IV or buccal, IM

67. 
PREVENTION
 ????

68. 3/27/2015 68