Chair person

Dr P.V. Venkataramanappa
Professor
Dept .of General medicine

Presenter
Dr Amar Patil
PG Gen Medicine
 Introduction
 Epidiemology
 Life cycle
 Clinical features
 Severe malaria
 Malaria in pregnancy
 Relapse
 Treatment of uncomplicated and complicated severe
malaria
 Chemoprophylaxis
 prevention
Introduction
 Malaria continues to pose a major public health threat
in india, particularly due to plasmodium falciparum.
 Malaria occurs mostly in the tropics. India harbours
both p.vivax and p.falciparum and contributes to 70% of
malarial cases in south-east asian regions.
  According to the World Malaria Report 2014, 22%
(275.5m) of India’s population live in high transmission
(> 1 case per 1000 population) areas, 67% (838.9m) live
in low transmission (0–1 cases per 1000 population)
areas and 11% (137.7m) live in malaria-free (0
cases) areas.
 In 2013, 0.88 million cases have been recorded, with
128 million tests being conducted on the suspected
cases, with P. falciparum causing 53% and P.
vivax causing 47% of the infections.
 The incidence of malaria in India accounted for 58% of
cases in the South East Asia Region of WHO

WHO. World Malaria Report 2014. WHO, Geneva. 2014

 At present, official figures for malaria in India,
available at NVBDCP, indicate 0.7–1.6 million
confirmed cases and 400-1,000 deaths annually.
 The biggest burden of malaria in India is borne by the
most backward, poor and remote parts of the country,
with >90-95% cases reported from rural areas and
<5-10% from urban areas.

Ashwani Kumar, Neena Valecha, Tanu Jain, Aditya P. Dash. Burden of Malaria in India:
Retrospective and Prospective View. Am J Trop Med Hyg. 2007;77(6_Suppl):69-78.
 The state of Orissa, with a population of 36.7 million
(3.5%), contributes about 25% of the total annual
malaria cases, more than 40% of P. falciparum malaria
cases and nearly 20–30% of deaths caused by malaria
in India.
 Followed by Meghalaya, Mizoram, Maharashtra,
Rajasthan, Gujarat, Karnataka, Goa, southern Madhya
Pradesh, Chhattisgarh, and Jharkhand that also report
significant number of malaria cases and deaths.

A Profile of National Institute of Malaria Research. Estimation of

True Malaria Burden in India
The parasite
 The malaria parasite is a mosquito transmitted
protozoan.
 Four species of the genus plasmodium infect the
humans, they are
 P.falciparum, p.vivax, p.ovale, p.malariae.
 Although infections with the fifth parasite
p.knowlesi, is an important cause of human
malaria in the islands of borneo and pennisular
malaysia.
Geographical aspects
 India is predominantly characterized by unstable
malaria transmission, which is seasonal with increased
intensity related to rain.
 Due to low or unstable malaria transmission dynamics,
most of the population has no or little immunity toward
malaria.
 Surveys have shown that in some people living in
malarious area mainly in forested areas.
Epidemiology
 The mosquito vector
 Malaria is transmitted by some species of anopheline
mosquites.
 The transmission does not occur at temperature below
16c, or above 33c and at altitudes >2000mts because
development in the mosquito cannot takes place.
 The optimum conditions for transmission are high
humidity and an ambient temperature between 20 and
30c.
The human host

 The behaviour of man also plays an important role in

the epidemiology of malaria. There must be a human
reservoir of viable gametocytes to transmit the
infection.
 In areas where there is long dry season, and malaria is
highly seasonal, the reservior for malaria transmission
is in people who asymptomatically harbour parasites
for long periods until the next rainy season.
Malaria parasite life cycle
 Infection with human
malaria begins when
feeding female anopheline
mosquito inoculates
plasmodial sporozites at
the time of feeding.
 The small motile
sporozites are injected
during the phase of
probing as the mosquito
searches for a vascular
space before aspirating
blood.
 After injection, they enter
the circulation, either
directly or via lymph
channels(approx 20%) and
rapidly target the hepatic
parenchymal cells.
 Each sporozite 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 merozites.
Period of Pre erythrocytic cycle
 P.vivax 8 days
 P.falciparum – 6 days
 P.malariae - 13 – 16 days,
 P.ovale 9 days
 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 relapses
which characterize infections with these two species.
 During the pre-erythrocytic or hepatic phase of
development considerable asexual multiplication takes
place and many thousands merozoites are released
from each ruptured infected hepatocyte.
Erythrocytic Schizogony
(asexual blood stage development)
 The merozoites liberated in the blood stream closely
resemble sporozoites. They are motile ovoid forms
which invade the red cells rapidly.
 Once inside the erythrocyte, the parasite lies within
the erythrocyte cytosol enveloped by its own plasma
membrane.
 During the early stages of development(<12hrs) the
small ‘ring forms’ of the four parasites appear similar
under light microscope.
 The young developing
parasite looks like a
signet ring or in case of
p.falciparum like a pair of
stereo headphones, with
darkly stained chromatin
in the nucleus and a
circular rim of cytoplasm.
Erythrocytic Schizogony
 Parasites are freely motile in the erythrocytes as they
grow they readily consume the contents within the
RBC mainly haemoglobin.
 As the proteolysis of the haemoglobin takes place
there is release of haem, it oxidizes to toxic ferric form.
 Intra parasitic toxicity is avoided by spontaneous
dimerization to an inert substance haemozion.
 This brown or blakish pigment can readily be seen
within the digestive vacuole of the growing parasite.
Erythrocytic Schizogony
 At approximately 12-14hrs of development,
p.falciparum erythrocyte membrane protein(pfEMP1)
on the exterior surface of the infected red cells which
mediate attachment of the infected erythrocytes to
vascular endothelium.
 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.
Erythrocytic Schizogony
 Eventually the growing
parasite occupies the entire
red cell which has become
spherical,depleted in
haemoglobin, and full of
merozoites.
 It then ruptures so that 6
to 36 merozoites are
released destroying the red
cells.
 The released merozoites
rapidly reinvade other red
cells and start a new
asexual cycle.
 p.falciparum p.vivax p.ovale p.malariae
Exoerythrocytic 5.5 8 9 15
cycle (days)
Erythrocytic 2 2 2 3
cycle
hypnozites no yes Yes No
Erythrocyte Young can Reticulocytes Reticulocytes Old RBCs
preference invade all ages
Sexual stages
 After a series of asexual cycles in p.falciparum, the
parasites develops into sexual forms(gametocytes)
which are long lived and motile.
 The process of gametocytogony takes about 7-10 days in
p.falciparum compared to p.vivax where it takes only 4
days.
 Merozoites differentiate into Male and female
gametocyte.
 One male (contains 8 microgametes) and one
female(macrogamete) are required for mosquito blood
meal for infection to occur.
Development in the mosquito
sporogony
 Following ingestion in the
blood meal of a biting female
anopheline mosquito, the male
and female gametocytes
become activated in the
mosquito’s gut.
 The male and female
gametocytes undergo rapid
nuclear division.
sporogony
 The motile male
microgametes separate and
seek female macrogamete,
fusion and meiosis then takes
place to form a zygote.
 Within 24 hrs enlarging
zygote becomes motile and
this forms the ookinete which
peneterates the wall of the
mosquito gut where it encysts
as an oocyst.
 The oocyst finally bursts to
liberate myriads of sporozites
into the coelomic cavity of the
mosquito.
• The sporozoites then
migrate to the salivary glands
to await inoculation into
next human host during
feeding.
• The development in the
mosquito takes about 8 and
35 days.
Expansion of the blood stage
infection
 When the hepatic schizonts rupture they liberate
approximately 103- 106 merozoites into the circulation
which then again infect the circulating red cells.
 For the first few stages the host is unware of the
brewing infection. May complain of vague non-
specific symptoms of malaise, headache, myalgia,
weakness or anorexia.
 The infection increases exponentially before settles
around a plateau then declines for several months
before finally being eliminated.
Clinical features in relation to
transmission intensity
 The clinical manifestations of malaria are dependent
on the previous immune status of the host.
 In areas of intense p.falciparum malaria transmission,
asymptomatic parasitaemia is usual in
adults.(premunition)
 Severe malaria never occurs in this age group it is
confined to the first years of life, and becomes
progressively less frequent with increasing age.
Clinical features in relation to
transmission intensity
 The rate at which age specific acquisition of
premunition occurs is proportional to the intensity of
malaria transmission.
 In areas with a constant high level p.falciparum
transmission, severe malaria occurs predominantly
between 6 months and 3 years of age, milder
symptoms are seen in older childrens, and adults are
usually asymptomatic and have a low parasitaemias.
Mixed species infection
 The incidence of mixed species infection is always under
estimated.
 In simultaneous infection with p.falciparum and p.vivax,
the former suppresses the latter, and the primary vivax
malaria infection may not appear until several weeks
later.
 The converse(p.vivax malaria with undiagnosed
coincident p.falciparum infection) occurs in
approximately 8% of cases.
Pyrogenic density
 The parasitaemia at which fever occurs is termed the
‘pyrogenic density’.
 The pryogenic density for p.vivax(<100parasites/ul) is
generally lower than that of p.falciparum(10000/ul).
 The pyrogenic density is a marker of immunity. High
progenic density indicates premunition, and a lower
risk of severe disease.
Uncomplicated malaria
 The cardinal feature of malaria is fever. The clinical
features of uncomplicated malaria are common to all
four species.
 P.malariae and possibly p.ovale both have a more
gradual onset than p.vivax.
 p.falciparum is unpredictable, onset ranges from
gradual to fulminant.
 The first symptoms of malaria are nonspecific and
resemble to influenza.
 Headache, muscular ache, vague abdominal
discomfort, lethargy and lassitude often precede fever
by up to 2 days.
 The temperature rises erraticaly at first with shivering,
mild chills worsening headache and loss of appetite.
 Cold stage: As the temperature rises there is intense
headache and muscular discomfort. The patient feels
cold, clutches at blankets and curls up shivering and
uncommunicative (the chill).there is peripheral
vasoconstriction.
 Hot stage: Within minutes the limbs begin to shake
and the teeth chatter and the temperature climbs
rapidly to a peak(between 39 and 41.5C). The rigor
usually lasts for 10-30 min.
 Sweating stage: By the end of rigor there is
vasodilation and the skin feels hot, a profuse sweat then
breaks out.
 If the infection is left untreated the fever in p.vivax and
p.ovale regularizes to a 2 day cycle(tertian) and
p.falciparum remain erratic for longer.
 P.malariae has an 72 hour life cycle, and so in an
untreated infection the paroxysm occurs on fourth day
termed as ‘quartan malaria’.
 P.flaciparum has a daily fever spike.(quotidian fever).
 The blood pressure is relatively low and there may be
symptomatic orthostatic hypotension.
 Defervescence usually takes 4-8hr.
 Paroxysms with rigors are more common in p.vivax
and p.ovale than in p.falciparum or p.malariae.
 If no treatment is given the natural infection stabilizes
for several weeks or months and then gradually
resolves.
 The duration of illness is proportional to the level of
immunity and differs between the parasite species.
 Pathophysiology of Clinical
features
 Anaemia
 Renal failure
 Fluid space and electrolyte changes.
 Pulmonary oedema
 Coagulopathy and thrombocytopenia.
 Blackwater fever
 Liver dysfunction
 Acidosis
 Hypoglycaemia
 Gastroinstestinal dysfunstion.
Anaemia
 The pathogenesis is multifactorial. It results from the
obligatory destruction of red cells containing parasites
at merogony.
 The shortened survival of red cells from which
parasites have been extracted by the spleen, and
accelerated destruction of non-parasitized red cells all
compunded by bone marrow dyserythropoeisis.
 In severe malaria anaemia develops rapidly because of
the rapid haemolysis of the red cells and decline in the
haematocrit.
Renal failure
 There is renal vasoconstriction and hypoperfusion in
severe falciparum malaria. The renal injury in severe
malaria results from acute tubular necrosis.
 ATN results from renal microvascular obstruction and
cellular injury consequent upon sequestration in the
kidney and the filtration of nephrotoxins.
Fluid space and electrolyte
changes.
 In view of the general vasodilatation and a falling
haemtocrit there will be increase in the plasme renin
activity, anti diuretic harmone concentrations
reflecting an appropriate homeostatic mechanisms to
maintain adequate circulating blood volume.
 Mild hyponaterima and hypochloremia are common
in sever malaria.
 Sreum potassium concentrations are usually normal.
Pulmonary oedema
 Pulmonary oedema in malaria results from a sudden
increase in pulmonary capillary permeability.
 The cause of this increase in the pulmonary
permeability is not exactly known, although the
presence of sequestered RBC and host leucocytes in
pulmonary capillaries may have a role in causing
pulmonar y capillary endothelial dysfunction.
 Acute renal failure, severe metabolic acidosis, and
coma are confined mainly to the falciparum malaria.
 Acute pulmonary oedema may also occur in vivax
malaria.
Coagulopathy and
thrombocytopenia
 In acute malaria coagulation cascade activity is
increased with accelerated fibrinogen turnover,
consumption of antithrombin III, reduced factor XIII
and increased concentrations of fribrin degardation
products.
 In severe malaria infections the antithrombin III,
protein S and protein C are further reduced and
prothrombin and partial thromboplastin times may be
prolonged.
 Thrombocytpenia is common to all the four malaria
species.
Blackwater fever
 In this condition there is massive intrvascular
haemolysis and the passage of ‘coco-cola’ coloured
urine.
 Blackwater(black urine) occurs in four circumstances;
1 When the pateint with G6PD deficiency take oxidant
drugs(ex.primaquine, sulphones or sulphonamides)
irrespective of wether they have malaria or not.
2 Occiasonally when G6PD deficiency patients have
malaria and receive quinine treatment.
3 In patients with severe falciparum malaria who have
normal erythrocyte G6PD levels irrespective of the
treatment given.
4 When people who are exposed to malaria self-
medication frequently with quinine.
 Blackwater fever may be associated with acute renal
failure, although in the majority of cases renal
function remains normal.
Liver dysfunction

 Jaundice is common in adults with severe malaria, and

there is other evidence of hepatic dysfunction with
reduced metabolic clearance of the antimalarial drugs
and failure of gluconeogenesis which contributes to
lactic acidosis and hypoglycaemia.
 Jaundice in malaria appears to have haemolytic,
hepatic and cholestatic components.
 Cholestatic jaundice may persist well into the recovery
period. There is no residual liver damage following
malaria.
Acidosis
 Acidosis is the major cause of death in severe
falciparum malaria, both in adults and children.
 In severe malaria the arterial, capillary, venous and
CSF concentrations of lactate rise in direct proportion
to disease severity.
 Lactate-pyruvate ratios often exceed 30, reflecting
tissue hypoxia and anaerobic glycolysis.
Gastroinstestinal dysfunstion
 Abdominal pain may be prominent in acute malaria.
 Minor stress ulceration of the stomach and duodenum
is common in severe malaria.

 The spleen
 Is often dark or black from malaria pigment, enlarged,
soft and firable.
 It is full of erythrocytes contaning mature and
immature parasites.
 Soft spleen is in acute infections and hard fibrous
enlargement associated with repeated malaria.
Hypoglycaemia
 Hypoglycaemia is an important manifestation of
severe malaria.
 An increased peripheral requirement for glucose
consquent upon anaerobic glycolysis, the increased
maetabolic demands of febrile illness.
 The obligatory use of glucose by parasite and failure of
hepatic gluconeogenesis and glycogenolysis.
Plancental dysfunction
 Pregnancy increases susceptibility to malaria. This is
probably caused by a supression of systemic and
placental cell mediated immune responses.
 There is intense sequestration of p.falciparum infected
erythrocytes in the placenta, local activation of pro-
inflammatory cytokine production and maternal
anaemia.
 This leads to cellular infiltration and thickening of the
syncytiotrophoblast and plancental insufficiency with
consequent fetal growth retardation.
 Malaria in Pregnancy : Double Trouble
 Malaria is more common in pregnancy compared to
the general population. Immuno suppression and loss
of acquired immunity to malaria could be the causes.
 Malaria in pregnancy being more severe, also turns out
to be more fatal, the mortality being double (13 %) in
pregnant compared to the non-pregnant population
(6.5%).
 Some anti malarials are contra indicated in pregnancy
and some may cause severe adverse effects. Therefore
the treatment may become difficult, particularly in
cases of severe P. falciparum malaria.

Meghna Desai, Feiko O ter Kuile, François Nosten, Rose McGready, Kwame Asamoa, Bernard Brabin, Robert
D Newman. Epidemiology and burden of malaria in pregnancy. Lancet Infect Dis 2007;7:93–104
 In pregnant women the morbidity due to malaria
includes anemia, fever illness, hypoglycemia, cerebral
malaria, pulmonary edema, puerperal sepsis and
mortality can occur from severe malaria and
haemorrhage.
 The problems in the new born include low birth
weight, prematurity, IUGR, malaria illness and
mortality.
Transfusion malaria
 Malaria can be transmitted by blood transfusion,
needle-stick injury, sharing of needles by infected
injection drug users.
 The incubation in this setting is often short because
there is no pre erythrocytic cycle .
 The clinical features are same as of naturally acquired
malarias.
 Radical therapy with primaquine is unnecessary in
transfusion related malaria.
Cerebral Malaria
 A strict definition of cerebral malaria has been
recommended for sake of clarity and this requires
the presence of unarousable coma, exclusion of
other encephalopathies and confirmation of P.
falciparum infection.
 This requires the presence of P.falciparum parasitemia
and the patient to be unrousable . And other causes
(e.g.hypoglycemia, bacterial meningitis and viral
encephalitis) ruled out.
 To distinguish cerebral malaria from transient
postictal coma, unconsciousness should persist for at
least 30 min after a convulsion. The deeper the coma,
the worse is the prognosis.
 If necessary, a lumbar puncture should be performed
to rule out bacterial meningitis.
 However, all patients with P. falciparum malaria with
neurological manifestations of any degree should be
treated as cases of cerebral malaria.
Neurological signs in cerebral
malaria:
 As per the definition, patient should have unarousable
coma, not responding to noxious stimuli with a
Glasgow coma scale of <7/15.
 Mild neck stiffness may be seen.
 Retinal haemorrhages occur in about 15% of cases.
 Pupils are normal.
 Corneal reflexes are preserved.
 Papilloedema is unusual and is a sign of poor
prognosis.
 Fixed jaw closure and tooth grinding(bruxism)
 The corneal reflexes are preserved except in case of
deep coma.
 Motor abnormalities like decerebrate rigidity,
decorticate rigidity and opisthotonus can occur.
 Deep jerks and plantar reflexes are variable.
 The patients may also have anemia, jaundice and
hepatosplenomegaly.
Investigations
 Lumbar puncture and CSF analysis may have to be done
in all doubtful cases and to rule out associated
meningitis.
observations Results
CSF Pressure Normal to elevated
Fluid Clear.
WBCs less than 10/µl.
protein and lactic acid Elevated
levels
 EEG may show non-specific abnormalities. CT scan of
the brain is usually normal.
Malarial Retinopathy:
 The malarial retinopathy
consists of four main
components:
1 Retinal whitening.
2 Vessel changes.
3 Retinal hemorrhages, and
4 Papilledema.
 The first two of these
abnormalities are specific to
malaria, and are not seen in
other ocular or systemic
conditions.
Algid malaria
 Algid malaria is characterized by hemodynamic
disorders as shock with pronounced metabolic
changes and hypothermia.
 A number of factors are involved in the development
of algid malaria. These include:
1. Pathological phenomena that are associated with the
changes in the state of red blood cells and lead to
impaired microcirculation (cytoadherence,
sequestration, rosetting);
 2. Tumor necrosis factor (TNF) that provokes
hypoglycemia, coagulopathy, and impaired
erythropoiesis.
 3. Altered acid-alkali balance with the development of
metabolic acidosis.
 4. Gastrointestinal lesion.
- Adherence of contaminated red blood cells in the
intestinal mucosal vessels induces epithelial ischemic
damage.
- Impaired absorption of liquid and its loss with
vomiting and diarrhea result in acute hypovolemia;
 Gram negative septicemia has been associated as an
important cause of hypotension in some cases of
falciparum infection.
 Gram-negative septicemia and possible sites of
associated infection should be sought in such patients,
e.g. lung, urinary tract (especially if there is an
indwelling catheter), meninges (meningitis),
intravenous injection sites, intravenous lines .
 The presenting feature in some cases of malaria, with a
systolic blood pressure less than 80 mmHg a cold,
clammy, cyanotic skin, constricted peripheral veins and
rapid feeble pulse.
 Severe hypotension can also develop suddenly in
patients with pulmonary edema, metabolic acidosis,
sepsis.
 massive hemorrhage due to splenic rupture or from the
gastrointestinal tract.
 Postural hypotension may be present.
 Hypovolumeia (due to reduced fluid intake, high
grade fever, sweating, vomiting and diarrhoea) also
may contribute to the reduced pressures..
 There may be reduction in visceral perfusion.
Septicemia, metabolic acidosis and hypoxia may result
in a drop in cardiac function.
Relapse
 Both p.vivax and p.ovale have a tendency to relapse after
resolution of the primary infection.
 Relapse must be distuinguished from recrudescene of
the primary infection because of the incomplete
treatment.
 P.falciparum is the usual cause of recrudescent
infections and tend to arise 2-4 weeks following
treatment . Where as relapses occur weeks or months
after the primary infection.
 The proportion of cases relapsing and the intervals
between relapses vary between strains. The pattern is
determined largely on the geographical orgin of
infections.
 Over 50% of cases of p.vivax in thailand relapse where
as in India the proportion is closer to 20%.
 The tropical strains have shorter intervals(3-6weeks)
compared to subtropical p.vivax which have long gaps.
 In a famous experiment conducted by Patrick Manson
in sept 1900, he infected his 23yr old son with p.vivax
through mosquitoes sent from rail from rome to
london.
 His son became ill with double tertian fever, but was
treated with quinine and recovered fully.
 In june 1901, he suddenly become ill again with p.vivax
malaria, a relapse interval of 9 months.
 In recent years a relapse interval of 6 weeks has been
quoted widely for p.vivax malaria.
 But this is an artefact of the use of chloroquine for the
treatment, which suppresses the first relapse. (at
3wks)
 Blood chloroquine levels decline by the time of 6weeks
and this is the first to manifest itself.
 The symptoms of a relapse start more abruptly than in
primary infection. They may begin with a sudden chill
or a rigor.
 Severe malaria

 Definitions of severe malaria are useful for clinical and

epidemilogical purposes.
 Definitions were proposed by WHO in 1990 and 2000.
 In severe malaria there is often evidence of multiple
organ dysfunction.
 More than one of the criteria are fulfilled. Pateints can
be treated for severe malaria even if they don’t fall
clearly into any of the criteria.
 Initial World Health Organization criteria from 1990

Manifestation Features
Cerebral malaria Unarousable coma not attributable to any other
cause, with a Glasgow Coma Scale score ≤9;
Coma should persist for at least 30 min after a
generalized convulsion
Severe anemia Hematocrit <15% or hemoglobin < 5 g/dl in the
presence of parasite count >10000/µl
Renal failure Urine output <400 ml/24 hours in adults and a
serum creatinine >265 µmol/l (> 3.0 mg/dl)
despite adequate volume repletion

Metabolic (Lactic) Metabolic acidosis is defined by an arterial blood

Acidosis/acidosis pH of <7.35 with a plasma bicarbonate
concentration of <22 mmol/L; hyperlactatemia is
defined as a plasma lactate concentration of 2-5
mmol/L and lactic acidosis is characterized by a
pH <7.25 and a plasma lactate >5 mmol/L.
Hypoglycemia Whole blood glucose concentration of less than
2.2 mmol/l (less than 40 mg/dl).
Manifestation
Pulmonary edema or
acute respiratory distress
syndrome (ARDS)
Hypotension and shock
(algid malaria)
Abnormal bleeding
and/or disseminated
intavascular coagulation
Repeated generalised
convulsions
Haemoglobinuria
features
Breathlessness, bilateral crackles, and other
features of pulmonary oedema. The acute
lung injury score is calculated on the basis
of radiographic densities, severity of
hypoxemia, and positive end-expiratory
pressure
Systolic blood pressure <70 mm Hg in
patients ≥5 years; cold and clammy skin or
0
a core-skin temperature difference >10
Spontaneous bleeding from the gums,
nose, gastrointestinal tract, retinal
haemorrhages and/or laboratory evidence
of disseminated intravascular coagulation.
≥3 generalized seizures within 24 hours
Macroscopic black, brown or red urine; not
associated with effects of oxidant drugs or
enzyme defects (like G6PD deficiency)
Added World Health Organization criteria from 2000
Prostration Extreme weakness, needs
support
Hyperparasitemia 5% parasitized erythrocytes or >
250 000 parasites/µl (in
nonimmune individuals
Investigations
 Microscopy : thin and thick smears
 Rapid diagnostic tests
 Polymerase Chain Reaction
 Immunofloroscence
 Light microscopy of thick and thin stained blood
smears remains the standard method for
diagnosing malaria.
 It involves collection of a blood smear, its staining
with Romanowsky stains and examination of the
Red Blood Cells for intracellular malarial parasites.
 Thick smears are 20–40 times more sensitive than
thin smears for screening of Plasmodium parasites,
with a detection limit of 10–50 trophozoites/μl.
 Thin smears allow one to identify malaria species
(including the diagnosis of mixed infections),
- quantify parasitemia, and assess for the
- presence of schizonts,
- gametocytes, and
- malarial pigment in neutrophils and monocytes.
 Jaswant Singh Battacharya (JSB) Stain for thick
and thin films: This is the standard method used by
the laboratories under the National Malaria
Eradication Programme in India.
Rapid diagnostic tests
 The introduction of simple, rapid, sensitive and
increasingly affordable dipstick or card tests for the
diagnosis of malaria has been a major advance in recent
years.
 These are based on antibody detection of malaria specific
antigens in blood samples.
1 Histidine-rich protein 2 of P. falciparum (PfHRP2)
2 Plasmodium aldolase
3 Parasite lactate dehydrogenase (pLDH)
 Histidine-rich protein 2 of P.
falciparum (PfHRP2)
- Is a water soluble protein that is produced by the
asexual stages and gametocytes of P.
falciparum, expressed on the red cell membrane
surface, and shown to remain in the blood for at least
28 days after the initiation of antimalarial therapy.
 Plasmodium aldolase is an enzyme of the parasite
glycolytic pathway expressed by the blood stages of P.
falciparum as well as the non-fa1ciparum malaria
parasites.
 Monoclonal antibodies against Plasmodium aldolase
are pan-specific in their reaction and have been used
in a combined ‘P.f/P.v’ immunochromatographic test
that targets the pan malarial antigen (PMA) along with
PfHRP2.
 Parasite lactate dehydrogenase (pLDH) is a soluble
glycolytic enzyme produced by the asexual and sexual
stages of the liver parasites and it is present in and
released from the parasite infected erythrocytes.
 It has been found in all 4 human malaria species, and
different isomers of pLDH for each of the 4 species
exist
 If the target antigen is
present in the blood, a
labeled antigen/antibody
complex is formed and it
migrates up the test strip to
be captured by the pre-
deposited capture
antibodies specific against
the antigens and against the
labeled antibody
 False Positivity: False positive tests can occur with
RDTs for many reasons. Potential causes for PfHRP2
positivity, include
1 Persistent viable asexual-stage parasitemia below the
detection limit of microscopy (possibly due to drug
resistance)
2 Persistence of antigens due to sequestration and
incomplete treatment, delayed clearance of
circulating antigen (free or in antigen-antibody
complexes) and
3 Cross reaction with non-falciparum malaria or
rheumatoid factor.
 False negativity: On the other hand, false
negative tests have been observed even in severe
malaria with parasitemias >40000 parasites/µl.
 This has been attributed to possible genetic
heterogeneity of PfHRP2 expression, deletion of
HRP-2 gene, presence of blocking antibodies for
PfHRP2 antigen or immune-complex formation.
 Sensitivity: RDTs for the diagnosis
of P.falciparum malaria generally achieve a
sensitivity of >90% at densities above 100 parasites
per µL blood and the sensitivity decreases
markedly below that level of parasite density.
Comparison of Peripheral Blood Smear Examination and RDTs for Malaria

Peripheral smear RDT’s

Test duration 20-60 minutes or 5-30 minutes
more
Test result Direct visualization Color changes on antibody
of the parasites coated lines
Capability Detects and Detects malaria antigens
differentiates all (PfHRP2/ PMA/pLDH) from
plasmodia at asexual and/or sexual forms
different stages of the parasite
Detection 5-10 parasites/µL 1 00-500/µL for
threshold of blood P. falciparum, higher for
non-falciparum
Species Possible Cannot differentiate among
differentiation non-falciparum species;
mixed infections
of P.falciparum and non-
falciparum appear
as P. falciparum
Quantification Possible Not possible
Approach to Malaria Diagnosis
 A clinician who faces a case of fever would need
answers to the following questions:
 Is it malaria?
 If yes;
 What is the species?
 Is it severe?
 Is it new/ recurrence?
 Is it active?
Approach to Malaria Diagnosis
Treatment
 Classification:
 Aryl amino alcohols: Quinine, quinidine (cinchona
alkaloids), mefloquine, halofantrine.
 4-aminoquinolines: Chloroquine, amodiaquine.
 Folate synthesis inhibitors: Type 1 – competitive inhibitors
of dihydropteroate synthase – sulphones, sulphonamides;
Type 2 – inhibit dihydrofolate reductase – biguanides like
proguanil and chloroproguanil; diaminopyrimidine like
pyrimethamine.
 8-aminoquinolines: Primaquine.
 Antimicrobials: Tetracycline, doxycycline, clindamycin,
azithromycin, fluoroquinolones.
 Peroxides: Artemisinin (Qinghaosu) derivatives and
analogues – artemether, arteether, artesunate, artelinic acid.
 Naphthoquinones: Atovaquone.
 According to anti malarial activity:
1 Tissue schizonticides for causal prophylaxis: These
drugs act on the primary tissue forms of the plasmodia
which grow within the liver.
Ex : Pyrimethamine and Primaquine.

2 Tissue schizonticides for preventing

relapse: These drugs act on the hypnozoites of P.
vivax and P. ovale in the liver that cause relapse of
symptoms on reactivation.
ex : Primaquine is the prototype drug.
3 Blood schizonticides: These drugs act on the blood
forms of the parasite and thereby terminate clinical
attacks of malaria.
Ex : chloroquine, quinine, mefloquine, halofantrine,
pyrimethamine, sulfadoxine, sulfones, tetracyclines
etc.
4 Gametocytocides: These drugs destroy the sexual
forms of the parasite in the blood and thereby prevent
transmission of the infection to the mosquito.
Ex : Chloroquine and quinine have gametocytocidal
activity against P. vivax and P. malariae.
- Primaquine has gametocytocidal activity against all
plasmodia, including P. falciparum.
 5 Sporontocides: These drugs prevent the
development of oocysts in the mosquito and thus
ablate the transmission. Primaquine and
chloroguanide have this action.
Treatment Aim
 Aims of Treatment
 To alleviate symptoms : Blood schizonticidal drugs
Chloroquine, quinine, artemisinin combinations
 To prevent relapses : Tissue schizonticidal drugs
Primaquine
 To prevent spread : Gametocytocidal drugs
Primaquine for P. falciparum, Chloroquine for all other
Treatment of uncomplicated malaria
FIRST-LINE DRUGS IN ENDEMIC AREAS
MALARIA DRUG TREATMENT
Known chloroquine sensitive Chloroquine 10mg base/kg stat followed by 5mg/kg
p.vivax, p.malariae, p.ovale, at 12, 24 and 36 hrs
p.falciparum or
Amodiaquine 10-12 mg base/kg/day for 3days.
Sensitive p.falciparum malaria Artesunate 4mg/kg per day for 3 days+
(Other than north eastern sulphadoxine 25mg/kg + pyrimethamine
states) 1.25mg/kg single dose.
( ACT-SP) OR
Artesunate 4mg/kg per day for 3
days+amodiaquine 10mg base/kg per day for 3 days.
Multi drug resistant Artesunate 4mg/kg per day for 3 days+ mefloquine
p.falciparum 25mg base/kg(8mg/kg per day for 3 days)
(In north eastern states) or
Artemether-lumefantrine 1.5/9 mg/kg twice daily
for three days.i.e adult dose is 4tabs b.d for 3 days.
(ACT-AL)
Radical treatment
Patients with p.vivax and p.ovale infections should also be given
primaquine 0.25 mg base/kg daily with food for 14 days to prevent relapse.

In mild G6PD deficiency 0.75 mg base/kg should be given once weekly for 6
weeks.
Primaquine should not be given in severe G6PD deficiency.
Treatment of mixed infections
(p.vivax + p.falciparum)
 All mixed infections should be treated with full course
of ACT and primaquine 0.25mg per kg body weight
daily for 14 days.
Mixed infections (p.vivax +p.falciparum)
In north eastern states Artemether-lumefantrine 1.5/9 mg/kg
twice daily for three days.i.e adult dose is
4tabs b.d for 3 days.(ACT-AL )+
primaquine 0.25mg/kg body wgt daily for
14 days.
In other states Artesunate 4mg/kg per day for 3 days+
sulphadoxine 25mg/kg +
pyrimethamine 1.25mg/kg single dose.
(ACT-SP) + primaquine 0.25mg/kg body
wgt daily for 14 days.
Treatment in pregnancy
 Anti malarials in pregnancy:
 All trimesters: Chloroquine; Quinine; Artesunate /
Artemether / Arteether
 2nd trimester: Mefloquine; Pyrimethamine /
sulfadoxine.
 3rd trimester: Mefloquine; ?Pyrimethamine /
sulfadoxine.
 Contra indicated: Primaquine; Tetracycline;
Doxycycline; Halofantrine
Treatment of uncomplicated
p.falciparum cases in pregnancy
Treatment of uncomplicated malaria
1st trimester Quinine salt 10mg/kg 3 times daily for 7 days.
Combined with clindamycin 10mg/kg twice daily.

2nd and 3rd trimester Artemether-lumefantrine 1.5/9 mg/kg twice

In north eastern daily for three days.i.e adult dose is 4tabs b.d for 3
states days.(ACT-AL )
In other states Artesunate 4mg/kg per day for 3 days+
sulphadoxine 25mg/kg + pyrimethamine
1.25mg/kg single dose. (ACT-SP)

 Primaquine should be avioded in pregnancy.

Assesment of therapeutic response
 Parasite clearance time(PCT)
- This is the interval between beginning of antimalarial
treatment and the first negative blood slide.
 Fever clearance time(FCT)
- This is the time from beginning of the antimalarial
treatment until the pateint is apyrexial.
- Approach is to record when temp first falls below 37.5c
and then when temperature falls and remains below
37.5c for 24 hours.
Clinical manifestations of severe
malaria
Manifestation/complications
Coma
Hyperpyrexia
Convulsions
Hypoglycaemia
Severe anaemia(HB <5gm/dl or PCV <15%)
Acute pulmonary oedema
Acute renal failure
Spontaneous bleeding and coagulopathy
Metabolic acidosis
shock
Chemotherapy of severe and
complicated malaria
Chloroquine sensitive
Chloroquine dihydrochloride 10mg base/kg body weight is
isotonic fluid IV over 8 hours followed 15mg/kg body weight
over next 24 hours. OR
Chloroquine dihydrochloride 5mg base/kg body weight in
isotonic fluid IV over 6 hours followed by 5mg/kg body
weight over next 30 hours. OR
If IV infusion is not possible chloroquine dihydrochloride
3.5mg base/kg body weight every 6 hours by IM or SC route.

Complete course of ACT should be administerd to all cases following

a paraenteral treatment as soon as oral treatment is feasible.
Chemotherapy of severe and
complicated malaria
Initial parenteral treatment for
atleast 48 hours
(Chloroquine resistant )
Quinine: 20mg quinine salt/kg body
wgt on admission(IV infusion or IM
divided doses ) followed by
maintainence dose of 10mg/kg 8th
hourly.
Artesunate : 2.4mg/kg IV on
admission(time =0) , then at 12 and
24hrs, then once daily.
Artemether : 3.2mg/kg body wgt IM
given on admission then 1.6mg/kg per
day.
Follow up treatment when the
patient can take oral medication
following parenteral
Full course of area specific ACT:
In north eastern states :
Artemether-lumefantrine 1.5/9
mg/kg twice daily for three days.i.e adult
dose is 4tabs b.d for 3 days (ACT-AL) for
3 days+ PQ single dose on second day.
In other states :
Artesunate 4mg/kg per day for 3
days+ sulphadoxine 25mg/kg +
pyrimethamine 1.25mg/kg single dose.
(ACT-SP) for 3 days+ PQ single dose on
second day.
Adverse effects and toxicity
Drugs Effects and toxixity
Artemisinin derivatives The most common toxic effects that have been
identified are nausea, vomiting, anorexia, and dizziness.
More serious toxic effects, including neutropenia,
anemia, hemolysis, and elevated levels of liver enzymes.
Embryotoxic effects : first trimester, congenital
abnormalities, stillbirths, and abortions.

Chloroquine At therapeutic doses, it can cause

- Dizziness, headache,
- Diplopia, disturbed visual accomodation,
- Nausea, malaise, and
- Pruritus of palms, soles and scalp.
- It can also cause visual hallucinations.
Quinine
 Quinine is a potentially toxic drug. The typical
syndrome of quinine side effects is called as
cinchonism.
 Mild cinchonism consists of ringing in the ears,
headache, nausea and disturbed vision. Functional
impairment of the eighth nerve results in tinnitus,
decreased auditory acuity and vertigo.
 Visual symptoms consist of blurred vision, disturbed
colour perception, photophobia, diplopia, night
blindness.
 Rashes, sweating, angioedema can occur.
 Quinine can also cause renal failure. Massive
hemolysis and hemoglobinuria can occur, especially in
pregnancy or on repeated use.
 Quinine stimulates insulin secretion and in
therapeutic doses it can cause hypoglycemia. This can
be more severe in patients with severe infection and in
pregnancy.
Sulfadoxine+Pyrimethamine
 Pyrimethamine can cause skin rashes depression of
hematopoiesis. Excessive doses can produce
megaloblastic anemia.
 Sulfonamides cause :
- Agranulocytosis.
- Aplastic anemia
- Hypersensitivity reactions like rashes, fixed drug
eruptions, exfoliative dermatitis.
- Serum sickness
- Liver dysfunction; anorexia, vomiting and acute
hemolytic anemia can also occur.
Mefloquine
 Less frequently it can cause
- Nightmares
- Sleeping disturbances
- Dizziness
- Ataxia
- Sinus bradycardia, sinus arrhythmia.
- Postural hypotension.
 Should be avioded in psychiatric diseases. And in first
trimester of pregnancy.
Atovaquone
 It may cause rash, fever, vomiting, diarrhoea and head
ache. Safety in pregnancy, lactation, children, and
elderly is yet to be established.
 Primaquine
 In therapeutic doses, primaquine is well tolerated. At
larger doses, it may cause occasional epigastric distress
and abdominal cramps.
 Patients with deficiency of Glucose 6-phosphate
dehydrogenase will develop hemolytic anemia on
taking usual doses of primaquine.
 Granulocytopenia and agranulocytosis are rare
complications.
Antimalarial treatment failure
Treatment outcome Symptoms and signs
Early treatment Development of danger signs or severe malaria on days 1-3
failure in presence of parasitaemia.
Parasitaemia on day 2 higher than day 0
Parasitaemia on day 3 >25% of count on day 0

Late treatment failure Development of danger signs or severe malaria after day 3
in the presence of parasitaemia without previously
meeting any of the criteria of early treatment failure.

Late clinical failure Presence of parasitaemia on any day from 4 to day 28 and
axillary temperature of >37.5c without previously meeting
any of the criteria of early treatment failure.

Adequate clinical Absence of parasitaemia on day 28 irrespective of axillary

response temperature without previously meeting any of the
criteria of early treat failure, late clinical failure.
Chronic complications of malaria
 Quartan nephropathy
 Hyper- reactive malarial splenomegaly
 lymphoma
Quartan nephropathy
 The pattern of renal involvement varies from
asyptomatic proteinuria to full-blown nephrotic
syndrome.
 Oedema, ascites or pleural effusions are usual
presenting features. Anaemia and
hepatosplenomegaly are common.
 The disease usually progresses to renal failure over 3-5
years.
 Antimalarial treatment does not prevent progression.
Hyper- reactive malarial
splenomegaly(tropical splenomegaly)
 Most pateints present with abdominal swelling and a
dragging sensation in the abdomen.
 The large, hard spleen is vulnerable to trauma and has
increased susceptibility to infections.
 HMS appears to be a premalignant condition
developing into lymphoma in some patients.
 The enlarged spleen usually regress over a period of
time with effective antimalarial prophylaxis.
Lymphoma
 In some countries Burkitt’s lymphoma is the most
common malignancy of childhood.
 It is an uncontrolled proliferation of B lymphocytes
and is associated with Epstein-Barr virus infections
and malaria.
 The EB virus cytotoxic T cell response is decreased
significantly during acute malaria and there is
increased proliferation of EB virus infected
lymphocytes. This may predispose to malignant
transformation.
chemoprophylaxis
 The National Vector Borne Disease Control
Programme (NVBDCP) recommends
chemoprophylaxis for selective groups in high P.
falciparum endemic areas
 Chemoprphylaxis is recommened for travellers from
non-endemic areas and pregnant women in endemic
areas.
 For longer stay of Military and Para-military forces in
high P. falciparum endemic areas, the practice of
chemoprophylaxis should be followed wherever
appropriate, e.g. troops on night patrol duty,
 Drug regimens for prophylaxis
Drug
Atovaquone/proguanil
Only in areas with
chloroquine or
mefloquine resistant P.f
Chloroquine phosphate
(Sensitive p.f strains)
Doxycycline(chloroquine
or mefloquine resistant
P.f)
Mefloquine
(Chloroquine resistant
areas)
National Drug Policy on Malaria – 2013. Directorate of National Vector Borne Disease Control Programme.
Govt. of India. New Delhi. 2013
Dosage Comments
250mg of atovaquone and Begin 1-2 days before and
100 mg of proguanil OD for 7 days after leaving
such areas.
300mg base once a week Begin 1-2 days before and
on the same day each for 4 weeks after leaving
week such areas.
100mg PO OD Begin 1-2 days before and
for 4 weeks after leaving
such areas
228mg base=250mg tablet Begin 1-2 days before and
1 tablet once a week on for 4 weeks after leaving
the same day each week. such areas
 Mefloquine is the only prophylactic drug advised for
pregnant women.
 This drug is generally considered safe in the second
and third trimesters of pregnancy.
 For pregnant women living in endemic areas(pf % >30)
IPTp(intermittent preventing therapy in pregnant
women) with sulphadoxine-pyrimethamine is
recommeneded.
Vaccines for Malaria
 This degree of protection would be extremely difficult
to achieve and might not be technically feasible with
current vaccine art and science.
 Many vaccine developers have therefore focused their
efforts on creating a vaccine that limits the ability of
the parasite to successfully infect large numbers of red
blood cells.
 This would not prevent infection but would limit the
severity of the disease and help prevent malaria
deaths.
Current Initiatives
 The PATH Malaria Vaccine Initiative and partner,
GlaxoSmithKline Biologicals, published recent Phase 2
trial results showing that the vaccine candidate,
RTS,S, has a promising safety and tolerability profile
and reduces malaria parasite infection and clinical
illness due to malaria.
 This was the first RTS,S vaccine trial in African infants.
Current successful Trails
 In Phase IIa trials, RTS,S/AS02 protected 40–86% of
malaria-naive individuals after artificial challenge.
 Phase IIb trials demonstrated a partial delay of infection,
a 30% reduction in clinical episodes of malaria, and
reduction in severe malaria by 58%.
 A phase III trial of RTS,S has been conducted in 11
countries of sub-Saharan Africa from March 2009
through January 2011, in 15460 children.
 The first results have shown a reduction in the total
number of episodes of clinical malaria by 55.1% and
reduction in severe malaria by 47%, both in the older
group.

The RTS,S Clinical Trials Partnership. First Results of Phase 3 Trial of RTS,S/AS01 Malaria Vaccine
in African Children. New Eng J Med. October 18, 2011. doi: 10.1056/NEJMoa1102287
Prevention
 Malaraia vector control measures
Action For individual and For community
family protection protection
Reduction of human Insecticide treated nets, Insecticide treated nets
mosquito contact repellents, protective
clothing
Destruction of adult Indoor residual
mosquitoes spraying, space spraying

Destruction of mosquito Domestic sanitation Larviciding of water

larvae surfaces, biological
control
Source reduction Small scale drainage Environmental
sanitation, drainage
management
Anti-adult measures
 Residual spraying : the spraying of houses with
residual insecticides(eg: DDT, malathion,
fenitrothion) is still most effective measure to kill the
adult mosquito.
 Space application : it involves the application of
pesticides in the form of fog or mist using special
equipment.
 Individual protection : man vector control can be
reduced by other preventive measures such as use of
repellents, protective clothing, bed nets.
Anti larval measures
 Larvicides : anti larval measures such as oiling the
collection of standing water.
 Source reduction : techniques to reduce mosquito
breeding sites which include drainage, flushing,
management of water level, intermittent irrigation.
References
 Parks textbook of preventive medicine. 23rd edition. The
malaria .pg 255-70.
 Harrisons principles of internal medicine.19th edition
 Mansons tropical diseases.22nd edition section
10,malaria.pg 1201-74.
 National Drug Policy on Malaria – 2013. Directorate of
National Vector Borne Disease Control Programme. Govt.
of India. New Delhi. 2013
 Meghna Desai, Feiko O ter Kuile, François Nosten, Rose
McGready, Kwame Asamoa, Bernard Brabin, Robert D
Newman. Epidemiology and burden of malaria in
pregnancy. Lancet Infect Dis 2007;7:93–104
 Ashwani Kumar, Neena Valecha, Tanu Jain, Aditya P.
Dash. Burden of Malaria in India: Retrospective and
Prospective View. Am J Trop Med
Hyg. 2007;77(6_Suppl):69-78.
 WHO. World Malaria Report 2014. WHO, Geneva.
2014
Thank you
 The recommendations for short term prophylaxis(less
than 6weeks) are as follows:
1 antimalarials that have to be taken daily should be
started one day before arrival in the risk area.
2 weekly chloroquine should be started 1 week before
arrival.
3 weekly mefloquine should be preferbly started 2-3
weeks before departure
4 All prophylactic drugs should be taken with unfailing
regularity for the duration of the stay in the malaria
risk area, and should be continued for 4 weeks after
the last possible exposure to infection.
 The recommendations for long term
prophylaxis(more than 6 weeks) are as follows
1 The person who has taken 300mg of chloroquine
weekly for over five years and requires further
prophylaxis should be screened twice yearly for early
retinal changes.
2 Mefloquine is contraindicated in cases with history of
convulsions, neuropsychiatric problems and cardiac
problems.
3 Available data on long term chemoprophylaxis with
doxycycline is limited.