MALARIA

DR. A.M IYAGBA

INTERNAL MEDICINE/NEUROLOGY
UPTH
 Lecture Outline
• Definition
• Epidemiology
• Life cycle
• Factors that affect susceptibility
• Pathogenesis
• Differences btw P. falciparum & other species
• Clinical features
• Special forms of malaria
• Diagnosis
• Treatment
• Prevention
 Definition
• Malaria is an acute systemic illness caused by
infection with Plasmodium falciparum, P
ovale, P vivax or P malariae all of which are
transmitted by the female anopheles
mosquito
 Epidemiology
• 300-800 million clinical cases annually
• 1-3 million deaths annually in the tropics and
sub-tropics
• Most deaths are in children.
• P falciparum is responsible for most deaths in
children less than 5 years.
• In Africa, Malaria causes an economic loss of
$12 billion annually.
 Pathogenesis
• Pathophysiology of malaria results from
destruction of erythrocytes (both infected &
un-infected), the consequent liberation of
parasite and erythrocyte material into the
circulation and host reaction to these events.
• P falciparum malaria infected rbcs specifically
sequester in the micro-circulation of vital
organs, interfering with microcirculatory flow
and host tissue metabolism
• Malaria parasites induce cytokines in much the
same way as bacterial endotoxin does
• A glycolipid material similar to bacterial
endotoxin is released on schizont rupture.
• Malaria antigen-related IgE complexes also
activate cytokine release.
• TNF-α, IL-1, IFN-ɣ are produced and inturn
release a cascade of pro-inflammatory
cytokines such as IL-8, IL-12 & IL-18
• These are balanced by the production of anti-
inflammatory cytokines such as IL-6 & IL-10.
• Cytokines are responsible for many symptoms and
signs of infection particularly fever & malaise.
• A pulse of TNF occurs at the time of schizont
rupture & is followed by the characteristic
symptoms and signs of the “paroxysm” ie shivering,
cool extremities, headache, chills, a spike of fever,
rigors followed by sweating, vasodilatation &
defervescence.
• Acute malaria is associated with high levels of
cytokines but the balance between pro-
inflammatory & anti-inflammatory differs in
response to severity.
• In severe malaria, pro-inflammatory cytokines
exceed anti-inflammatory cytokines.
• IL-12 & TGF-β1 regulate the balance between
these two groups of cytokines
 Other roles of cytokines in malaria pathogenesis

• Placental dysfunction

• Suppresion of erythropoiesis

• Inhibition of gluconeogenesis

• Cause fever

• Mediate parasite killing

 Sequestration & cytoadherence
• Erythrocytes containing mature forms adhere
to the vascular endothelium & disappear from
the circulation.
• Cytoadherence is mediated by several ligands:
• P.falciparum erythrocyte membrane protein 1
or PfEMP1
• Intracellular adhesion molecule (ICAM1)- from
vascular endothelium
Differences between P falciparum & other
agents that cause malaria
• P vivax & P ovale can have prolonged (up to 3 years) liver
stages.
• P vivax differs from all others in that its merozoites
cannot attack rbcs that lack the Duffy blood group
antigen.
• P falciparum, P ovale., P vivax takes aproximately 48
hours to complete asexual erythrocytic stage of their life
cycle and are called Tertian (recurring every 3rd day)
malarias.
• P malaria takes 72 hours to do this as is called Quartan
(recurring every 4th day) malaria
• Only P falciparum infects erythrocytes of all
ages leading to high levels of parasitaemia.
• Only P falciparum secretes proteins that form
knobs on the surface of infected erythrocytes
that bind to vascular endothelium and infect
the microcirculation of the brain, kidneys and
intestines leading to severe malaria
 Clinical features
• First symptoms are non-specific:
-lack of sense of well being
-headache
-fatigue
-abdominal pain
-myalgia then fever.
• These symptoms are similar to those of most
viral illnesses
• Nausea, vomitting and orthostatic
hypotension are common.

• Anaemia is common in children

• Splenomegaly is common in young adults

• Petechiae may occur with P falciparum

 Stages of malaria febrile paroxysms
• The classical malaria paroxysms of fever, chills and
rigors are unusual and occur with P vivax or P ovale.
• 3 stages of the fever paroxysm occur:
• “Cold stage”-occurs 15-60 mins before fever onset
during patient feels cold & has shaking chills.
• “Hot stage”-body temp is btw 39-41 C
• “Sweating stage”-about 2-6 hours after stage 2
characterized by marked diaphoresis, resolution of
fever, profound fatigue with desire to sleep
 Severe falciparum malaria
• Appropriately treated, uncomplicated Plasmodium
falciparum malaria has a mortality of 0.1%
• Severe falciparum malaria has a mortality of 3%
• It is characterized by vital organ dysfunction or the
presence of asexual parasitaemia of 3%.
• The clinical, parasitologic and laboratory features
of severe malaria are shown below and presence
of these is an indication for ICU admission.
 Severe malaria
• 1. Cerebral malaria
• 2. Renal
• 3. Pulmonary oedema
• 4. Fluid & elctrolytes changes
• 5.Anaemia
• 6. Black water fever
• 7. Coagulopathy & thrombocytopenia
• 8.Acidosis
 Black water fever
• Poorly understood condition with massive intravascular
haemolysis & passage of coca-cola coloured urine.
• It occurs in 3 conditions:
1. When patients with G6PD take oxidant drugs (eg
primaquine or sulphonamides) irrespective of whether
they have malaria
2.Occasionally when G6PD deficient patients have
malaria and receive quinine treatment
3.Some patients with severe quinine treated falciparum
malaria who have normal G6PD levels
 Malaria in pregnancy
• In hyperendemic areas, malaria in primigravid &
secungravid women is associated with low birth
weight (<1700g) & increased neonatal mortality.
• Maternal HIV infection predisposes pregnant
women to malaria and predisposes their newborns
to congenital malaria & LBW[low birth weight].
• Pregnant women are more prone to developing the
complications of severe malaria.
 Transfusion malaria
• Malaria can be transmitted by blood
transfusion, needle stick injury, intravenously
from iv drug abusers and from organ
transplantation.
• The incubation period is very short because
there is no pre-erythrocytic phase of
development.
• Clinical features & treatment are same for
naturally aquired malaria.
 Hyperreactive malarial splenomegaly
• Chronic or repeated malarial infections produce
hypergammaglobulinaemia, normocytic normochromic
anamia and splenomegaly.
• This is due to an abnormal immune response to malaria
antigens that is characterized by
-massive splenomegaly
-hepatomegaly
-marked elevation in serum titres of IgM
-elevated malaria antibodies
-hepatic sinusoidal lymphocytosis
-peripheral B lymphocytosis (in Africa)
• It is associated with the production of cytotoxic
antibodies to CD4+ cells, CD8+ cells and an
increase in the ratio of CD4+ to CD8+ cells.
• Vulnerability to skin & respiratory infections is
increased.
• Many patients die of overwhelming sepsis
• Such patients should receive malaria
prophylaxis for life
 Quartan malarial nephropathy
• Chronic or repeated infections with P malariae
& possibly other malarial species, may cause
immune complex injury to the renal glomeruli
resulting in nephrotic syndrome.
• Histologic appearance is that of focal or
segmental glomerulonephritis with splitting of
capillary basement membrane.
• It usually responds poorly to treatment with
either antimalarials, steroids or cytotoxics.
 Burkitt’s lymphoma & Epstein-Barr virus
infection
• It is possible that malaria related
immunosuppression promotes infection with
lymphoma viruses.

• Burkitt’s lymphoma is strongly associated with

EBV.

• The prevalence of this tumor is high in

malarious areas of Africa.
 Diagnosis of malaria
• I. Tests to establish diagnosis
1. Microscopy
2. Rapid detection tests
3. Polymerase chain reactions
• II. Tests to show extent of disease or complications
1.FBC +ESR
2.E/U/Cr
3.FBS
4. Liver function test
5.Chest X-ray
6. Abdominal USScan
 Microscopy
• Microscopy is done after staining thick & thin
films.
-Thick film-for parasite species determination
-Thin film for parasite density (no of
parasitized rbc/1000 rbcs in a thin film
-Giemsa stain at Ph 7.2 is preferred.
-Wrights, Fields or Leishmann’s can also be
used.
• In a patient suspected of having malaria with a
negative blood film, the blood film should be
examined every 12hrs for 36-48 hrs before
considering it to be negative.

• An expert microscopist can detect as few as 5

parasites/µL blood.
 Rapid antigen detection tests
• These are rapid, simple, sensitive & specific
antibody based diagnostic stick or card test (RDTs)
detect P falciparum specific histidine-rich protein
(HRP) 2.
• These tests remain positive for several weeks
after acute infection
• This is a disadvantage in high transmission areas
where infections are highly prevalent
• RDTs can detect approx. 50 parasites/µL. of blood
• Full blood count
-Normocytic-normochromic anaemia is usual
-Leucocyte count is normal but may be raised in
severe infections.
-thrombocytopenia rarely
• Acute-phase reactant proteins such as ESR & CRP
are usually high.
• Abdominal USScan-splenomegaly, hepatomegaly
• Others EUCr, Liver function tests, HIV screening
 Treatment of malaria
• Objective of treating severe malaria is to save
life!

• Objective of treating uncomplicated malaria is

to prevent development of complications and
cure the infection

• Classes of antimalarials-4 groups basically

 1.Quinoline-like or quinoline-related
compounds
• Act by chemically interfering with
intraparasitic heme detoxification, preventing
the dimerization process that results in the
formation of hemozoin (malaria pigment)

• E.g: Quinidine, chloroquine, amodiaquine,

mefloquine, halofantrine, lumefantrine,
piperaquine.
• Primaquine & tafenoquine are structurally
related 8-aminoquinolines that kill the liver
and sexual stages of P. falciparum and all
stages of P. vivax, P. ovale & P. malariae
 2. Antifols
• These competitively inhibit plasmodial
dihydrofolate reductase.

• They are synergestic with sulfonamides and

sulphones.

• E.g: Pyrimethamine, trimethoprim, proguanil

 3. Artemisinin compounds
• These are endoperoxides extracted from the
naturally occuring artemisinin plant
• They inhibit plasmodial ATPase 6 (a calcium
ATPase)
• They produce the most rapid therapeutic
response.
• E.g: artemisinin, dihydroartemisinin,
artemeter, artesunate)
 4. Atovaquone
• This is a potent inhibitor of cytochrome-
mediated electron transport.

• It is synergistic with proguanil

• Several antibacterial drugs also have anti-
plasmodial activity.
• Their action is slow
• Used only in combination with the
antimalarials
• Those used are Tetracyclines, Macrolides,
Lincosmides, Sulphones & Sulphonamaides.
 Classification of patients for Rx
• 1. Uncomplicated malaria

• 2. Severe malaria
 Uncomplicated Malaria
• WHO recommends artesunate-based combination therapy
(ACT) for treatment.

• These combinations include:

1. Artesunate-pyrimethamine-sulphadoxine
2. Artesunate-lumefantrine
3. Artesunate-Amodiaquine
4. Artesunate-mefloquine

If pregnant, avoid artesunate in first trimester

 Severe malaria
• Currently, four parenteral agents are used for the
treatment of severe malaria:
-Artesunate

-Artemether

-Quinine

-Quinidine
 Drugs used for prophylaxis
• Atovaquone/proguanil (Malarone)
-Contains 250 mg Atovaquone & 100mg proguanil
-1 tablet daily
-Begin 1-2 days b4 entering an endemic area and
continue for 7 days after leaving
• Doxycycline:100 mg daily
• Chloroquine phosphate
-300mg base (500 mg salt orally once/week)
-Begin 1-2 weeks b4 entering endemic area & continue
for 4 weeks after leaving
 Prevention of malaria
1. Insecticide treated nets (ITN)
2.Intermittent preventive treatment (IPT)
-Preferred approach in pregnancy
-Involves giving full curative Rx doses of an effective
antimalarial drug, preferably at single doses during
pregnancy, beginning in the 2nd trimester after
quickening
3.Indoor residual spraying
4.Chemoprophylaxis
5.Malaria vaccine-still at developmental stage
Imena ! Nagode!

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