Malaria

 Came from the

word “mal” “aria”
or bad air
 Still the world’s
most important
tropical parasitic
disease
 Epidemiology
 Public health problem in 90 countries (2.4 billion people)

 Worldwide prevalence: 300 – 500 M cases annually

 More than 90%: Subsaharan-Africa

– remaining 2/3 are in India, Brazil, Sri Lanka, Afghanistan,
Vietnam, and Colombia

 Western Pacific Region : 10 endemic countries –

– Cambodia China
– Lao People’s Democratic Republic Malaysia
– Papua New Guinea Philippines
– Republic of Korea Solomon Islands
– Vanatu Vietnam
 Malaria continues to be a major global
health problem
– over 40% of the world's population (> 2400
million people) are exposed to varying degrees of
malaria risk in some 100 countries

 with modern rapid means of travel large

numbers of people from nonmalarious areas
are being exposed to infection which may
only seriously affect them after they have
returned home.

Management of severe malaria

A practical handbook
2nd edition WHO Geneva 2000
Epidemiology in the Philippines

 65/78 provinces are endemic

 11.3 M Filipinos at risk ( 14.8%)
– Farmers, indigenous cultural groups, miners, forest
product gatherers, and soldiers
 Ranks as one of the ten leading causes of
morbidity in the country
 Highly endemic province:
– Palawan, Kalinga Apayao, Ifugao, and Agusan del
Sur
 Summary of Reported 2002 Malaria Data: Philippines

Indicator 2002 Data

Population at risk for malaria 6 458 708
Confirmed malaria cases 37 005
Incidence rate per 1000 population 0.5
P. falciparum cases 22 831
Malaria deaths 71
Probable malaria cases 19 489
Severe malaria cases 1 103
Proportion of risk population protected by ITNs 8% (2001)
(insecticide-treated nets)
 Malarial species
Species older newer
designation designation

malignant falciparum
falciparum
tertian malaria
vivax benign tertian vivax malaria

ovale ovale tertian ovale malaria

malariae quartan quartan

Causal Agents:
 Blood parasites of the genus Plasmodium. 
 approximately 156 named species of
Plasmodium which infect various species
of vertebrates. 
 Four are known to infect humans:
– P. falciparum >90% of human cases
– P. vivax
– P. ovale  and
– P. malariae.
 In the Philippines more than 70% is
caused by P. falciparum
– Less than 30% by P. vivax
– Less than 1% by P. malariae
 P. ovale – reported in Palawan in the
1960s
 Peak transmission: beginning and at
the end of the rainy season
 Malarial species
Differences between the species include:
 blood-stage morphology
 minor life cycle variations
– P. vivax and P. ovale exhibit the hypnozoite stage and
can cause true relapses
– trophozoite- and schizont-infected erythrocytes of P.
falciparum sequester in the microvasculature and are
not found in the peripheral circulation
 host erythrocyte preference
– P. vivax and P. ovale prefer reticulocytes (immature
erythrocytes)
– P. malariae prefers senescent erythrocytes
– P. falciparum exhibits no preference
 disease and clinical manifestation
 Malarial species
Key Morphological Differences Between Human Plasmodium Species
in Blood Smears

falciparum vivax ovale malaria

o numerous e
o enlarged o similar to o compac
rings erythroc P. vivax t
o smaller yte o compact parasit
rings o Schüffne trophozoi e
o no r's dots te o merozoi
trophozoit o 'ameboi o fewer tes in
es or d' merozoit rosette
schizonts trophozo es in
o crescent- ite schizont
shaped o elongate
gametocyt d
es erythrocy
Vector

Anopheles Mosquito
Vector
 Philippines:
– Anopheles minimus var.
flavirostris
 Night biter
 Prefers to breed in slow, flowing, partly
shaded streams that abound in foothill
areas
 Occasionally, they utilize new habitats
such as irrigation ditches, rice fields,
pools and wells
 Horizontal flight : 1 – 2 km
 Vector
 Philippines:
– Anopheles litoralis
 In coastal areas of Mindanao, particularly
Sulu
– Anopheles maculates
 Coexists with A. flavirostris in the portions
of streams exposed to sunlight
 Appear to be responsible for malaria
transmission in high altitudes
– Anopheles mangyanus
 Has the same breeding habitats and
seasonal prevalence as A. flavirostris
 Prefers habitat located in forest fringes
Larvae of Anopheles gambiae, the major malaria vector in Africa
•can breed in very diverse habitats
•three habitats are shown from left to right: tire tracks, rice
fields, and irrigation water
Other modes of transmission of
Malaria
 Blood transfusion from infected
donors
 Contaminated needles and
syringes
 Congenital
 Life cycle
 Asexual cycle: occurs in
humans
– Schizogony: leads to
formation of merozoites
– Gametogony : leads to
formation of the gametocytes
 Sexual cycle : occurs in the
mosquitoes
– Sporogony: leads to the
formation of sporozoites
Life Cycle
 Some merozoites of P. vivax and P. ovale
re-invade the liver cells forming
hypnozoites  these dormant exo-
erythrocytic forms may remain quiet for
years
 Reactivation of the hypnozoite forms lead
to relapse
– Cold, fatigue, trauma. Pregnancy, infections,
other illnesses may precipitate reactivation
 Pathogenesis
 Pathological processes are the result of the
erythrocytic stage

 Once merozoites invade the erythrocytes cells

reduce deformability

 In the course of invasion, electron dense

submembranous structures appear and enlarge
and become “knobs”.
– KNOBS : important in cytoadhesion
 They contain several proteins such as rosettins,
riffins, histidine-rich protein and the P. falciparum
erythrocyte membrane protein (PfEMP-1) - - which is
the most adhesive of the knobs
 Pathogenesis
 Infected erythrocytes also undergo membrane
transport mechanisms
 Hemoglobin is digested forming hematin, and
variant strain-specific neoantigens are
expressed
 Soluble antigens of P. falciparum are potent
inducers of pro-inflammatory cytokines 
stimulates release of TNF or cachexin which
causes of malarial fever
– Result of the release of cytokines at the time of
Schizont rupture : fever, febrile paroxysms,
headache, various aches and pains
Pathogenesis
 Altered red cell surface membranes +
host’s immunological response to the
parasite antigens  pathologic
changes  alteration in regional blood
flow and in the vascular endothelium,
altered biochemistry, anemia, and
tissue and organ hypoxia
Clinical manifestations
 Prepatent period: the interval of time
from sporozoite injection to detection
of parasites in blood
– 11 days to 4 weeks
– P.falciparum : 11-14days
– P.vivax : 11 – 15 days
– P. ovale – 14 – 26 days
– P. malariae: 3 to 4 weeks
 Clinical manifestations
 Incubation period: The time between
sporozoite injection and the appearance
of clinical symptoms
– Typically 8 to 40 days depending on the
species ( 9 days to 3 years)
 P. falciparum: 8-15days P. vivax 12-20 days
 P. ovale 11-16 days P. malariae 18-40days
– Depends on parasite strain, dose of
sporozoites inoculated, immune status of the
host, malaria chemoprophylaxis history
Clinical manifestations
 There are no absolute diagnostic
clinical features except for the regular
paroxysms of fever with asymptomatic
intervals
 Prodromal symptoms: feeling of
weakness and exhaustion, a desire to
stretch and yawn, aching bones, limbs,
loss of appetite, nausea and vomiting,
a sense of chilliness
Clinical manifestations
 3 stages of classical malaria paroxysms:
total duration of a typical attack  8 to
12 hours
– COLD STAGE: starts with sudden
inappropriate feeling of coldness and
apprehension  violent teeth shattering and
shaking of the whole body
 Intense peripheral vasoconstriction despite
increased core temperature
 These rigors last 15 to 60 minutes
 Clinical manifestations
 HOT STAGE:
– Flush phase
– Patient becomes hot and manifests with headache,
palpitations, tachypnea, epigastric discomfort, thirst,
nausea and vomiting; confused and delirious; skin is
flushed and hot
– Temp. 40C – 41C
– 2 – 6 hours
 SWEATING STAGE:
– Defervescence or diaphoresis ensues with profuse
sweating
– Temp lowers within the next 2-4 hours and
symptoms diminish
 Malaria paroxysms
 These paroxysms will exhibit periodicities of 48 hours for
P. vivax, P. ovale, and P. falciparum, and a 72-hour
periodicity for P. malariae.

 Initially the periodicity of these paroxyms may be irregular

as the broods of merozoites from different exoerythrocytic
schizonts synchronize.
– This is especially true in P. falciparum which may not
exhibit distinct paroxysms, but exhibit a continuous
fever, daily attacks or irregular attacks (eg., 36-48 hour
periodicity).

 Patients may also exhibit splenomegaly, hepatomegaly

(slight jaundice), and hemolytic anemia during the period
in which the malaria paroxysms occur.
 Malignant tertian

Benign tertian

Quartan
 Recrudescence: renewal of parasitemia
and/or clinical features arising from
persistent undetectable asexual
parasitemia in the absence of an exo-
erythrocytic cycle

 Relapse: renewed asexual parasitemia

following a period in which the blood
contains no detectable parasites
– Occur with P.vivax and P. ovale are due to
reactivation of hypnozoites in the liver
Recurrent infections in malaria are of 3 types:
 Relapse: occur as a result of delayed
maturation of the dormant liver stages
 Recrudescence: occurs when parasitemia
caused by the same parasite responsible for
initial infection recurs after clearance or a
significant reduction in the initial
parasitemia
– Occurs most commonly with P. falciparum because
of drug resistance
 Reinfection: with diff parasites, as well as
infection with more than one type, occurs in
areas with a high intensity of transmission
Feign: Textbook of Pediatric Infectious Diseases
5th edition
Classical signs and symptoms

Triad of :
 ANEMIA

 FEVER AND
CHILLS
 SPLENOMEGALY
 Complications
Cerebral Malaria: complication of severe
P. falciparum malaria
 a diffuse encephalopathy with loss of
consciousness
– consciousness ranges from stupor to coma
– onset can be gradual or rapid
– unresponsive to pain, visual, and verbal stimuli
 associated with sequestration in cerebral
microvasculature
Complications
 Other signs of severe malaria
– Severe anemia
– Thrombocytopenia
– Renal failure
– Pulmonary edema
– Hypoglycemia
– Circulatory collapse/shock
 Diagnosis
• Microscopic identification of the malarial
parasites in thick and thin blood smears stained
with Giemsa or Wright’s stain : gold standard
• Obtain smears every 6 to 8 hrs
• Quantitative Buffy Coat (QBC)
• uses a specially prepared capillary tube coated with
acridine orange; only screens presence of malarial
parasites
• Rapid malaria diagnostic tests (RDTs)
 Prognostic indicators
Clinical indicators of poor prognosis
 Age under 3 years
 Deep coma
 Witnessed or reported convulsions
 Absent corneal reflexes
 Decerebrate/decorticate rigidity or opisthotonos
 Clinical signs of organ dysfunction (e.g. renal
failure, pulmonary edema)
 Respiratory distress (acidosis)
 Circulatory collapse
 Papilledema and/or retinal edema
 Prognostic indicators
Laboratory parameters of poor prognosis
 Hyperparasitaemia (>250 000/µl  Blood urea more than 60 mg/dl
or >5%)  Serum creatinine more than 265
 Peripheral schizotemia µmol/l (>3.0 mg/dl)
 (Peripheral blood  High CSF lactic acid (>6 mmol/l)
polymorphonuclear
leukocytosis (>12 000/µl) and low CSF glucose
 Mature pigmented parasites  Raised venous lactic acid (>5
(>20% of parasites) mmol/l)
 Peripheral blood  More than 3-fold elevation of
polymorphonuclear leukocytes serum enzymes
with visible malaria pigment (aminotransferases)
(>5%)  Increased plasma
 Packed cell volume less than 5'-nucleotidase
15%
Haemoglobin concentration Low antithrombin III levels
less than 5 g/dl  Very high plasma
 Blood glucose less than 2.2 concentrations of tumour
mmol/l (<40 mg/dl) necrosis factor (TNF)
Laboratory Diagnosis : THICK AND THIN BLOOD SMEARS

 Thick films: place a drop of

blood in the middle of a clean
microscope slide and with the
corner of a second slide
spread the drop until it is
about 10-15mm in diameter.
The thickness should be such
that it is just possible to see
news print through it.

 Thin films are made in the

standard manner. Allow the
films to dry, do not leave on
the bench in a laboratory
which is not fly proofed,
otherwise the film will be
eaten.
 Microscopic findings
 Ring: early developmental stage of the asexual
erythrocytic parasite; the ring is a young trophozoite.
– the term is derived from the morphologic appearance
of this stage, which includes chromatin (red),
cytoplasm (blue), often arranged in a ring shape
around a central vacuole;
 Trophozoite: next developmental stage
– has lost its "ring" appearance, and has begun to
accumulate pigment (colored yellow to black).
 Schizont: late developmental stage
– has begun its division into merozoites, and thus is
characterized by the presence of multiple contiguous
chromatin dots (to be distinguished from multiple
chromatin dots from multiple infections, which tend
not to be contiguous).
 Gametocyte: sexual erythrocytic stage
Diagnostic points:
 Red Cells are not
enlarged.
 Rings appear fine and
delicate and there may be
several in one cell.
 Some rings may have two
chromatin dots.
 Presence of marginal or
applique forms.
 It is unusual to see
developing forms in
peripheral blood films.
 Gametocytes have a
characteristic crescent
shape appearance.
However, they do not
usually appear in the
blood for the first four
weeks of infection.
 Maurer's dots may be
present.
 P. falciparum
 Growing
trophozoite
showing
Maurer's cleft
Diagnostic points:-
 Red cells containing
parasites are usually
enlarged.
 Schuffner's dots are
frequently present in the
red cells as shown
above.
 The mature ring forms
tend to be large and
coarse.
 Developing forms are
frequently present.
 Schuffner’s
dots
 P. vivax
Diagnostic points :- 
 Ring forms may have a
squarish appearance.
 Band forms are a
characteristic of this
species.
 Mature schizonts may
have a typical daisy
head appearance with
up to ten merozoites.
 Red cells are not
enlarged.
 Chromatin dot may be
on the inner surface of
the ring.
Diagnostic points :-
 Red cells enlarged.

 Comet forms common

(top right)
 Rings large and
coarse.
 Schuffner's dots, when
present, may be
prominent.
 Mature schizonts
similar to those of P.
malariae but larger and
more coarse.
 In oval malaria caused
by Plasmodium ovale,
the red cells infected
by oval-shaped
trophozoites reveal
Schuffner's spots.
The red cells with
ring form become
oval in shape.

 Oval malaria is seen

mostly in the
subsaharan Africa.
Blood stages malarial
parasites
Blood Smears 
Fig.1.normal
red cell
2-
18:trophozoit
es
(Fig.2-10
ring-stage
trophozoites)
19-26:
schizonts
(fig26
ruptured
schizont)
27, 28:
mature
macrogameto
cytes (female)
29, 30:
Plasmodium
falciparum:
Blood Stage
Parasites:
Thick Blood Smears
malariae:
Blood Stage
Parasites:
Thin Blood
Smears

fig. 1: Normal
red cell
2-5: young
trophozoites
(rings)
6-
13:trophozoites
14-22: schizonts
23: developing
gametocyte
24:macrogamet
ocyte
(female)
25:
microgametocyt
e
Plasmodium malariae
Blood Stage Parasite
Thick Blood Smears
blood stage
parasites:
Thin Blood
Smears
Fig. 1: Normal
red cell
2-5:young
trophozoites
(Rings)
6-15:
trophozoites
16-23: schizonts
24:
macrogametocy
tes
(female)
25:
microgametocyt
e
parasites:
thin blood
smears 
Fig.1: Normal
red cell
2-6:young
trophozoites
(ring stage
parasites)
7-18:
trophozoites
19-27:
schizonts
28-29:
macrogametocy
te
(female)
30:
microgametocyt
e
Plasmodium falciparum
ction of mosquito showing oöcysts(1) and sporozoites
ection of liver showing a greatly enlarged parenchym
ell full of merozoites (see arrow).
on of brain showing blood vessels blocked with develo
ciparum parasites (see arrows).
Approach to Diagnosis
 history of being in endemic area
 symptoms: fever, chills, headache,
malaise, splenomegaly, anemia
 microscopic demonstration of parasite
(blood smear)
 antigen detection (ParaSight-F,
OptiMal)
Treatment
 The main uses of antimalarial drugs:
2. Protective (prophylactic)
3. Curative (therapeutic)
4. Preventive
 Treatment
 Prophylaxis: used before the infection
occurs or before it becomes evident
– Aim: preventing either the occurrence of the
infection or any of its symptoms
– Blood schizonticides

 Curative or therapeutic : refers to action

on the established infection which uses
blood schizonticidal drugs for the
treatment of the acute attack and in the
case of relapsing malaria, radical
treatment of the dormant liver forms
Treatment
 Prevention of transmission:
– means deterrence of mosquitoes with the
use of gametocytocidal drugs to attack
the gametocytes in the blood of the human
host.
– Also means interruption of the
development of the sporogonic phase in
the mosquito when it feeds on the blood of
an infected person who has been given
appropriate sporonticidal drugs
 Treatment
Drug Class Examples
Fast-acting blood choloroquine (+other 4-aminoquinolines),
schizontocide quinine, quinidine, mefloquine,
halofantrine, antifolates
(pyrimethamine,

proquanil,sulfadoxine,dapsone),
Slow-acting blood artemisinin
doxycyclinederivatives (quinhaosu)
(+ other tetracycline
schizontocide antibiotics)

Blood + mild tissue proquanil, pyrimethamine, tetracyclines

schizontocide
 Treatment
Drug class Example
Tissue primaquine
schizontocide (anti-
relapsing)

Gametocidal primaquine, artemisinin derivatives, 4-

aminoquinolines (limited?)

Combinations Fansidar (pyrimethamine+sulfadoxine),

Maloprim (pyrimethamine + dapsone),
Malarone (atovaquone + proquanil)
 Drug resistance is defined
by a treatment failure and
can be graded into different
levels depending on the
timing of the recrudescence
following treatment (Figure)

 Traditionally these levels of

drug resistance have been
defined as:
– Sensitive (no
recrudescence)
– RI (delayed
recrudescence)
– RII (early
recrudescence)
– RIII (minimal or no
anti-parasite
RI
 Mildest form of resistance
 Characterized by initial clearance of the
parasites but recrudescence occurs within a
month after the start of treatment
 Classified as early: clearance occurs for the first
48 hours and recrudescence takes place within
the first 14 days after start of treatment
 Late : clearance within the first 48 hours and
recrudescence occurs within the 14th to 28th day
RII
 Shows initial reduction in parasitemia after
treatment but there is failure to clear the blood
of asexual parasites and soon after, increase of
parasitemia occurs
RIII
 Severest form of resistance
 Parasitemia either show no significant change
with treatment or will increase
Treatment
 A modified protocol based on clinical
outcome was introduced by WHO in
1996.
– In this protocol the level of resistance is
expressed as adequate clinical response
(ACR), late treatment failure (LTF), or
early treatment failure (ETF) as defined
by the following:
Treatment
 ACR, absence of parasitemia
(irrespective of fever) or absence of
clinical symptoms (irrespective of
parasitemia) on day 14 of follow-up
 LTF, reappearance of symptoms in the
presence of parasitemia during days 4-
14 of follow-up
 ETF, persistence of clinical symptoms
in the presence of parasitemia during
the first 3 days of follow-up
 Prevention and Control
reduce human-mosquito contact
 impregnated bednets

 repellents, protective clothing

 screens, house spraying

reduce vector
 environmental modification

 larvicides/insecticides

 biological control

reduce parasite reservoir

 case detection and treatment

 chemoprophylaxis
 Drug prophylaxis
Drug Prophylactic Breakthrough
resistance drug drug
None Chloroquine Pyrimethamin
e and
Chloroquine Doxycycline sulfadoxine
Pyrimethamin
e&
Chloroquine sulfadoxine
plus Doxycycline
pyrimethamin or Mefloquine
e-sulfadoxine Quinine SO4
tablet plus
tetracycline
Prophylaxis
 Taken during the duration of the stay
and continued until 4 weeks after the
last possible exposure to infection
 Chloroquine – for areas where malaria
is exclusively due to P. vivax and
where ther is low risk of chloroquine-
resistant P. falciparum
 Mefloquine, doxycycline or
atovaquone/proguanil – areas where
levels of resistance to chloroquine are
high
Massive increase in spleen size in hyperreactive splenomegaly
due to malaria.
 Nephrotic
syndrome
secondary to
chronic infection
with Plasmodium
malariae. Notice
the swollen face
and ascites.
 Plasmodium falciparum. In cerebral
malaria, numerous petechiae appear in
the brain.