1. MALARIA

2. Why The Concern About Malaria?
> 1/3rd
of world’s population (2.1 billion) live in
MALARIOUS areas
One million deaths (mostly African children) in 2008
Malaria can decrease GDP by 1.3% in countries with
high disease rates
Non-immune travelers very vulnerable to the
disease.
WHO FactSheet April 2010.

3. Concern……contd.
1.5 Million laboratory confirmed cases annually
Half cases are due to P. falciparum
Rising resistance to Chloroquine (CHQ)
Avilability of Rapid Diagnostic Tests (RDT)
National Drug Policy on Malaria, NVBDC. 2010.

4. Malarial Endemecity in India
In most parts of the country
about 90%, malaria is unstable.
In North-Eastern States
efficient malaria transmission is
maintained during most
months of the year.
Intermediate level of stability is
maintained in eight states
(Andhra Pradesh, Jharkhand,
Gujarat, Madhya Pradesh,
Chhatisgarh, Maharashtra,
Orissa and Rajasthan).
http://www.searo.who.int/

5. Transmission
Man is the only important reservoir
Vector is female Anopheles mosquito
Temperature: > 68º F and < 86º F,
Rainfall: thrive in tropical areas
Altitude: rarely exist above 2000 meters (e.g. J&K)
Terrain: coastal areas and lowlands with lots of freshwater
breeding sites
Transmission also possible through:
Blood transfusion (Short incubation period)
Contaminated needle
Organ transplant
Congenital (<5% of newborns of infected mothers)

6. Pathogenesis
RBC destruction
Immune complexes and mediators
Capillary permeability
Tissue hypoxia

9. Acute Symptoms
Parasites density reach about 50 per micro liter
Classical cyclic paroxysm:
Cold stage: chills and shaking (15-60 minutes)
Hot stage: warm, headache, vomiting (2-6 hours)
Sweating stage: weakness (2-4 hours)
Feel well for period of time, then cycle repeats itself

10. Severe Malaria
Most of these are attributable to P. falciparum (90
percent), but P. vivax and P. knowlesi can also cause
severe disease

11. Severe Falciparum Malaria
Also known as Complicated malaria or
Malignant Tertian malaria
Mortality rate of ~0.1% - appropriately treated,
uncomplicated falciparum malaria
Mortality rate >30% - multiple vital organ
dysfunction
A hospital study from Jabalpur showed that 27%
of severe malaria were having cerebral malaria of
whom 1/4th
died.
Journal, Indian Academy of Clinical Medicine
Vol. 2, No. 3 July-September 2001

12. Profile of severe malaria in India
Characteristics Frequency Mortality
Cerebral malaria 76% 22%
Severe anemia 34% 56%
Hypoglycemia 21% 40%
Jaundice 15% 57%
Renal failure 8% 75%
Blackwater fever 6% 66%
Algid malaria 4% 50%
Indian Pediatrics 2003; 40:939-945

13. Severe Falciparum Malaria
Presence of asexual parasitaemia + ≥ 1 of the following
Cerebral malaria/unarousable coma :
• Not attributable to any other cause in a patient with falciparum
malaria.
• Coma should persist for at least 30 minutes after a generalized
convulsion.
Severe anemia :
• Normocytic normochromic anemia with haematocrit < 15% or
• hemoglobin < 5 gm/dl
Renal failure :
• Urine output < 400 ml/24 hrs (adults) and < 1.2 ml/kg/hr (children)
• No improvement with rehydration and
• S. creatinine level > 3 mg/dl.
Working group of WHO,2001

14. Severe Falciparum Malaria (cont…)
Acute respiratory distress syndrome (ARDS)
Hypoglycemia
 < 40 mg/dl (2.2mmol / l)
Hypotension/shock (Algid malaria):
 Systolic B.P. < 50 mmHg in children aged 1-5 years or
 < 80 mmHg in adults, with cold, clammy skin
Bleeding/disseminated intravascular coagulation (DIC)
Convulsion : Repeated generalized convulsions > 2 within 24 hrs, despite
cooling.
Acidosis/acidaemia :
 Arterial pH < 7.25 or plasma bicarbonate level of < 15 mmol/l.
 Venous lactate level of > 15 mmol/l.
Macroscopic haemoglobinuria
(According to the working group of
WHO,2001)

15. Who is at risk for complicated malaria?
High-transmission areas,
Young children,
Pregnant females and
Visitors (of any age) from non-endemic areas.
Non-transmission / low-transmission areas
Travelers returning, with undiagnosed malaria
infection, from any area where P. falciparum
transmission occurs.

16. The processes involved are
Sequestration
• Cytoadherence(Pf EMP1)
• Vascular endothelial ligands
 ICAM in brain,
 chondroitin sulfate in placenta and
 CD36 in most other organs
• Rosetting
• Decreased RBC Deformability
Inflammatory response

17. The standard clinical case definition of cerebral
malaria includes the following criteria
Blantyre coma score ≤2
P. falciparum parasitemia (any density)
No other identifiable cause of coma (eg,
hypoglycemia, meningitis, or a post-ictal state)
( WHO guidelines for the treatment of malaria. Geneva, World Health Organization, 2010.}

18. 
 Score
 Eye movement
 Watches or follows
 1
 Fails to watch or follow
 0
 Best motor response
 Localizes painful stimulus
 2
 Withdraws limb from painful stimulus
 1
 No response or inappropriate response
 0
 Best verbal response
 Cries appropriately with pain, or, if verbal, speaks
 2
 Moan or abnormal cry with pain
 1
 No vocal response to pain
 Total Fully conscious children score 5; children who do not respond to painful stimuli score 0. Response to pain should be assessed via firm nailbed pressure,
sternal pressure, and pressure over the supraorbital ridge. Blantyre coma score ≤2 is associated with mortality.
 Molyneux, ME, Taylor, TE, Wirima, JJ, Borgstein, A. Clinical features and prognostic indicators in paediatric cerebral malaria: a study of 131 comatose Malawian
children. Q J Med 1989; 71:441


19. Cerebral Malaria
Clinical feature Children (African) Adults
Onset Rapid Insidious
Seizures
More common
(in 80%)
In 20 %
Neurological
signs
Brainstem signs, raised
ICP,retinal changes
Symmetrical upper
motor neuron signs
Mortality 18.6% 20%
Sequelae 11% <5%
Lancet Neurol 2005; 4: 827–40

20. Malarial Retinopathy
Common in children with
cerebral malaria(60%)
Papilloedema, and multiple
retinal hemorrhages
Whitening of the macula
(spares the central fovea),
peripheral retina and retinal
vessels
Bad prognostic indicator
Lancet Neurol 2005; 4: 827–40

21. Acute renal failure (ARF)Pathogenesis
Renal cortical vasoconstriction
 Micro vascular obstruction due to sequestration
 Dehydration and hypovolemia (reversible)
 Massive intravascular hemolysis in blackwater fever
Common in adults, rare in children
Manifests as ATN (renal cortical necrosis never
develops)

22. Black water fever
Earlier, mortality was high (20% to 30%)
Presently, mortality is much lower.
Black or dark brown or red urine
Transient
Resolves without complications (mostly).
In severe cases ATN develops from massive
hemolysis.
Transfused blood is also rapidly haemolysed
where plasma may also be red.
The patient often has a slate grey appearance.

23. Anemia
Results from
Accelerated red cell destruction
Removal by the spleen
Ineffective erythropoiesis.

24. Metabolic acidosisCauses:
renal failure
primary lactic acidosis (more common)
Lactic acidosis results from :
Anaerobic glycolysis due to micro vascular obstruction.
Failure of hepatic and renal lactate clearance.
Production of lactate by the parasite.
Venous lactate concentration
BEST PROGNOSTIC INDICATOR (4 hours after
admission)
>5mmol/l has bad prognosis
Trans R Soc Trop Med Hyg. 1994 Jan-Feb;88(1):67-73

25. Hypoglycemia• Caused by:
o ↑ requirement due to anaerobic glycolysis.
o ↑ metabolic demands of febrile illness.
o Obligatory demand of parasites.
o Failure of hepatic gluconeogenesis and glycogenolysis
o Quinine stimulated insulin secretion
Occurs in 8% of adults and 30% of children (particularly
problematic in pregnant women and children)
Poor prognosis. Mortality rate as high as 40%.

26. Pulmonary edema/ARDS
May develop even after several days of
antimalarial therapy
Results from increase in pulmonary vascular
permeability which is not reflected in other
vascular beds.
Cause of increased permeability is not known
Mortality >80%

28. Diagnosis
Clinical diagnosis
Lab. Diagnosis
Microscopy
Thick film - presence/absence
Thin film - morphology/species
Fluorescent microscopy (acridine orange)
Capillary – fluorescence (QBC assay)
Other Rapid Diagnostic Tests (RDTs)
Antigen capture( pfHRP2, pLDH)
 PCR

29. Microscopic diagnosis
Gold standard
Sensitivity : 5-10 parasites/μl
Thick smear : rapid diagnosis
Thin smear : species identification
Other advantages:
Platelets, toxic granules, anemia
If negative, repeat 6 times 6 hourly.
Indian pediatrics 2005

30. Microscopy….contd..
Collection of blood sample
before administration of antimalarials
not necessarily during fever
Examination done in 100x oil immersion using
giemsa stain, minimum of 100 fields examined
before concluding slide negative

31. Microscopy….contd..
o Why parasites not detected in peripheral smear ?
o sequestration in deep vascular bed
o partially treated patients
o prophylactic antimalarial treatment
o inexperienced microscopist
o poor quality staining
o Slide Positivity Rate lower in 1-3 yrs age group
Indian pediatrics 2005/ June 1999

32. Rapid Diagnostic Tests
Histidine-rich protein 2 of P. falciparum
water soluble protein, produced by the asexual
stages/gametocytes of P. falciparum, expressed on the
RBC surface.
remain in the blood for at least 28 days after the
initiation of antimalarial therapy
detect asexual parasitemia of >40 parasites/µL
Sensitivity 92.7% Specificity 99.2%
In AIIMS study 97% & 100% (Indian J. Med. Res. Jan
1999)
Limitations:
 Doesn’t detect P. vivax
 Positivity after treatment (from 6 to 31 days )
 Cross-reaction between RA factor and HRP2 antigen
Lancet Infect Dis 2006; 6: 582–88

33. Rapid Diagnostic Tests….contd..
Plasmodium aldolase
Enzyme of the parasite glycolytic pathway
expressed by the blood stages of all Plasmodium : pan-
specific: the pan malarial antigen (PMA)
Parasite lactate dehydrogenase (pLDH)
glycolytic enzyme produced by live parasites
different isomers of pLDH for each of the 4 species exist
detect a parasitemia of >100 to 200 parasites/µL

35. The Quantitative Buffy Coat (QBC)Test
 Glass haematocrit tube, pre-coated with acridine orange is filled
with 55-65 μl of blood with a precisely made cylindrical float
suspended in it.
 Centrifugation at 12,000 rpm separates cells based on their
densities which form wide bands due to the float
 RBC containing Plasmodia are less dense, concentrate just below
the leukocytes, at the top of the erythrocyte column
 Parasites contain DNA, takes up the acridine orange stain, appear
as bright specks of light under fluorescent light
 Sensitivity of 83% and specificity of 94%
 Very useful to detect ≤100 parasites/μl of blood
J Commun Dis. 1999 Mar;31(1):19-22.
WBC
RBC
RBC with Plasmodium

36. PCR & ELISAPolymerase chain reaction (PCR)
10-fold more sensitive than microscopy,
Sensitivity to detect 1.35 to 0.38 parasites/µL for P.
falciparum and 0.12 parasites/µL for P. vivax
Sensitivity of 95% and specificity of 99%
ELISA
Antibodies to asexual blood stages appear a few days after
malarial infection and are undetectable in 3-6 months
after treatment.
Sensitivity of 78.1% and specificity of 94.9%
Lancet Infect Dis 2006; 6: 582–88

37. Flow cytometry
It detects a metabolic end-product of plasmodium in
WBCs (DiOC1), or parasite DNA (Hoechst 33342)
Found to be useful in indicating a diagnosis of
malaria during routine blood counts with
automatizer.
Sensitivity 95% and specificity of 88%.
Cytometry. 2001 Oct 1;45(2):133-40.

38. Upcoming techniques
Intraleucocytic malaria pigment
Pigment-containing neutrophil count is a marker of
disease severity in childhood malaria (Trans R Soc Trop
Med Hyg. 1998 (Jan-Feb); 92(1):54-56)
Mass spectrometry
Sensitivity of 10 parasites/µL of blood

40. Guiding factors
Treatment should be guided by three main factors:
The infecting Plasmodium species,
The clinical status and age of the patient,
The drug susceptibility of the infecting parasites as
determined by the geographic area where the
infection was acquired.

41. Aims of treatment
Providing complete cure (clinical and parasitological) of
malaria cases
 Prevention of progression of uncomplicated malaria into
severe malaria and thereby reduce malaria mortality
 Prevention of relapses by administration of radical
treatment
 Interruption of transmission of malaria by use of
gametocytocidal drugs
 Preventing development of drug resistance by rational
treatment of malaria cases
National Drug Policy on Malaria, NVBDC. 2010.

42. ACT:
artemether + lumefantrine
Artesunate plus amodiaquine/ mefloquine/
sulfadoxine-pyrimethamine (available in India)
dihydroartemsinin + piperaquine (DHA+PPQ) (NA in
India)
Second-line antimalarial treatment:
alternative ACT known to be effective in the region
AS plus tetra/doxy/ clinda for 7 days
quinine plus tetra/doxy/ clinda for 7 daysGuidelines for the treatment of malaria. 2nd
ed. WHO. 2010

43. Treatment of severe malaria
AS: 2.4 mg/kg IV or IM (0, 12 and 24 h and then once a
day), or,
Quinine: 20 mg/kg (may be omitted) on admission (IV
infusion or divided IM injection) followed by 10 mg/kg 8
hourly (infusion rate should not exceed 5 mg salt/kg per
hour), or,
Artemether: 3.2 mg/kg IM given on admission and then 1.6
mg/kg per day (IM drug has erratic absorption, hence, less
preferred)
Parenteral treatment in severe malaria cases should be
given for minimum of 24 hours
National Drug Policy on Malaria, NVBDC. 2010.
Guidelines for the treatment of malaria. 2nd
ed. WHO. 2010

44. Treatment of severe malaria
After parenteral artemisinin therapy, patients will
receive a full course of oral ACT for 3 days
Those patients who received parenteral Quinine
therapy should receive:
Oral Quinine 10mg/kg three times a day for 7 days
(including the days when parenteral Quinine was
administered) + Doxy 3mg/kg once a day or Clinda
10mg/kg 12-hourly for 7 days (Doxy is contraindicated
in pregnant women and children under 8 years of age),
or,
ACT
National Drug Policy on Malaria, NVBDC. 2010.

45. Antimalarial Combination
therapy
Antimalarial combination therapy (CT) : simultaneous
use of two or more blood schizonticidal drugs with
different biochemical targets in the parasites and
independent modes of action
Artemisinin-based combination therapy (ACT) is
antimalarial combination therapy with an artemisinin
derivative as one component of the combination

46. Rationale for ACT
Widely established resistance to chloroquine and
sulfadoxine-pyrimethamine;
Theoretical basis of CT are:
 Protect individual drug against occurrence of resistance
 To decrease rate of decline in efficacy
 Interrupt spread of resistant strains
 Decrease transmission in a region

47. Why Artemisinins?
● Short half-life hence good for combination
● Rapid substantial reduction of the parasite biomass
● Rapid resolution of clinical symptoms
● Effective action against multi-drug resistant P. falciparum
● Reduction of gametocyte carriage
● Few reported adverse effects

48. For children, artesunate 2.4 mg/kg BW IV or IM given
on admission (time = 0), then at 12 h and
24 h, then once a day is the recommended treatment.
Artemether, or quinine, is an acceptable
alternative if parenteral artesunate is not available:
artemether 3.2 mg/kg BW IM given on
admission then 1.6 mg/kg BW per day ; or quinine 20
mg salt/kg BW on admission (IV infusion or divided
IM injection), then 10 mg/kg BW every 8 h; infusion
rate should not exceed 5 mg salt/kg BW per hour

49. Intravenous artesunate has been shown to
significantly reduce the risk of death from severe
malaria compared
to intravenous quinine (6 trials, 1938 participants; RR
0.62, 95% CI 0.51–0.75; high quality evidence).
Intravenous artesunate was associated with a lower
risk of hypoglycaemia (2 trials, 185 participants; RR
0.46, 95% CI 0.25–0.87; low quality evidence

50. Among 1461 patients in Bangladesh, India, Indonesia,
and Myanmar randomized to receive artesunate or
quinine, lower mortality was observed among those
who received artesunate (15 versus 22 percent,
respectively; risk reduction 34 percent
( Dondorp A, Nosten F, Stepniewska K, et al. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial.
Lancet 2005; 366:717.)
Among 5425 children in Africa with severe malaria
randomized to receive therapy artesunate or quinine, lower
mortality was observed among those who received
artesunate (8.5 versus 10.9 percent, respectively; risk
reduction 22.5 percent)
 Dondorp AM, Fanello CI, Hendriksen IC, et al. Artesunate versus quinine in the treatment of severe falciparum malaria in African
children (AQUAMAT): an open-label, randomised trial. Lancet 2010; 376:1647.

51. Degree of resistance (WHO)
Smears on day 2, 7 and 28 are done to grade the
resistance as R1 to R3.
In a case of normal response parasite count to fall to
25% of pre-treatment value by 48 hours and smear
should be negative by 7 days.

52. Drug resistance of P. falciparum
http://www.searo.who.int/
The drug resistance of P. falciparum
to chloroquine is widespread.
However for SP, low to moderate level
resistance is observed in north-east
states, in kolar district in Karnataka, and
one district each in Madhya Pradesh
and West Bengal respectively.
Quinine resistance is limited to few
places of North-East states only.

53. Classification of Treatment Outcome
1. Early treatment failure (first 3 days),
2. Late treatment failure (4th
-28th
day)
 Late clinical failure,
 Late parasitological failure, and
1. Adequate clinical and parasitological response.
 Absence of parasitemia on day 28 irrespective of axillary
temperature without previously meeting any 0f the criteria of
treatment failure
Assessment and monitoring of antimalarial drug efficacy for the treatment of
uncomplicated falciparum malaria. Geneva, World Health Organization, 2003
(document WHO/HTM/RBM/2003.50)

54. Early t/t failure
 danger signs/sev. malaria in day 1-3 + parasitaemia
 day 2 parasitaemia > day 0 count irrespective of axillary temp
 parasitaemia on day 3 with axillary temperature ≥ 37.5o
C
 day 3 parasitaemia ≥ 25% of day 0
Late t/t failure
 Late clinical failure
 danger signs/severe malaria > day 3 + parasitaemia, w/o previously
meeting any of the criteria of early treatment failure
 parasitaemia + axillary temperature ≥ 37.5o
C (or history fever) (day 4-28),
w/o previously meeting any of the criteria of early treatment failure.
 Late parasitological failure
 Parasitaemia (day 7-28) + axillary temperature < 37.5o
C, w/o previously
meeting any of the criteria of early treatment failure

55. OTHER SUPPORTIVE MEASURES

56. SUPPORTIVE MEASURESIf there is suspicion of meningitis in a case of ?
cerebral malaria, LP should be done
In malaria endemic areas particularly, where
parasitaemia is common in the young age group, it is
often impossible to rule out septicaemia in a shocked
or severely ill obtunded child.
Blood culture
Empirical antibiotic treatment

57. SUPPORTIVE MEASURES
Anemia
Ideally fresh blood should be transfused
In high transmission settings, for children with a
haemoglobin level of <5 g/100 ml (haematocrit <15%)
In low-transmission settings, a threshold of 20%
(haemoglobin 7 g/100ml) is recommended.

58. Acute renal failure (ARF)
Management
Correction of dehydration
Diuretic therapy
Hemodialysis is preferred over peritoneal dialysis
If facilities are not available for hemodialysis, peritoneal
dialysis can still be tried.
If ARF >2 days, maintenance dose of quinine should be
reduced by 30 to 50% while artemisinin or chloroquine
require no change

59. Exchange blood transfusion (EBT)The rationale :
Removing infected red blood cells and lowering the parasite
burden
Reducing rapidly both the antigen load and the burden of parasite-
derived toxins, metabolites and toxic mediators produced by the
host;
Replacing the rigid unparasitized red cells by more deformable
cells and therefore alleviating microcirculatory obstruction.
Carries a significant risk
Although only the circulating relatively non-pathogenic
stages are removed – and this is also achieved rapidly with
artemisinin derivatives

60. Exchange Transfusion
Has not been proven beneficial in an adequately
powered randomized controlled trial
CDC recommends for persons with a parasite density
of more than 10% or if complications such as cerebral
malaria, non-volume overload pulmonary edema, or
renal complications exist.
The parasite density should be monitored every 12
hours until it falls below 1%, which usually requires
the exchange of 8-10 units of blood in adults.

61. Poor Prognostic indicatorsClinical indicators
● 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
● Papilloedema and/or retinal changes
World Health Organization. In : Management of severe malaria
– A practical handbook. 2nd edition. Geneva. 2000; 1-69.

62. Poor Prognostic indicatorsLaboratory indicators
Hyperparasitaemia
leukocytosis (>12 000/μl)
Mature pigmented parasites (>20% of parasites)
Peripheral blood polymorphonuclear leukocytes with visible
malaria pigment (>5%)
High CSF lactic acid (>6 mmol/l) and low CSF glucose
Raised venous lactic acid (>5 mmol/l)
More than 3-fold elevation of serum enzymes
(aminotransferases)
Increased plasma 5'-nucleotidase
Low antithrombin III levels
Very high plasma concentrations of (TNF) >100pg/ml
World Health Organization. In : Management of severe malaria
– A practical handbook. 2nd edition. Geneva. 2000; 1-69.

63. Take Home Message
Incidence of P. falciparum malaria and complicated
malaria is rising in India
Antimalarial resistance is wide spread and increasing
Don’t give presumptive treatment
Use ACTs for uncomplicated falciparum malaria
Don’t use monotherapies
In India artesunate-amodiaquine is suitable (areas with
CQ and SP resistance, but not MDR)

64. Take Home Message
Artesunate is better than quinine in severe malaria
(new dose schedule)
Use high loading dose of quinine (20 mg/kg)
For vivax malaria chloroquine is to be used as
resistance is not wide spread
Use Primaquine for 14days for radical cure in P.
VIVAX
Newer drugs and vaccine are new rays of hope

65. Dr Surya Kumar

66. Classification of Treatment Outcome