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MALARIA
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.
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.
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/
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)
Pathogenesis
RBC destruction
Immune complexes and mediators
Capillary permeability
Tissue hypoxia
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
Severe Malaria
Most of these are attributable to P. falciparum (90
percent), but P. vivax and P. knowlesi can also cause
severe disease
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
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
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
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)
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.
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
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.}
   
 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
   
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
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
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)
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.
Anemia
Results from
Accelerated red cell destruction
Removal by the spleen
Ineffective erythropoiesis.
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
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%.
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%
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
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
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
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
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
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
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
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
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.
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
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.
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.
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
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
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.
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
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
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
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
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
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.
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.
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.
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)
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
OTHER SUPPORTIVE MEASURES
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
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.
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
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
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.
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.
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.
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)
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
Dr Surya Kumar
Classification of Treatment Outcome

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Malaria . dr surya

  • 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
  • 7.
  • 8.
  • 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%
  • 27.
  • 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
  • 34.
  • 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
  • 39.
  • 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
  • 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

Editor's Notes

  1. Malaria has had a huge impact on civilization throughout history, and continues to do so now. It is the most prevalent disease in the world. About 2 billion people live in malarious areas throughout the world and there are 100 to 300 million new cases each year. About 1 to 3 million people die from Malaria each year. Malaria kills more people each year than any other communicable disease except Tuberculosis.
  2. The only important host reservoir for Plasmodium is Man. The vector is the female Anopheles mosquitoes. The female needs blood for egg development; male mosquitoes don ’ t feed on blood. To transmit the parasite, the mosquitoes must be able to breed, feed on humans, and live long enough for the parasite to complete its life cycle. Any place that harbors Anopheles mosquitoes is potentially at risk for malaria. However, certain environmental conditions must exist for the parasite to survive. -Temps between 68-86 o F (20 o and 30 o C). Plasmodia don ’ t survive below average temps of 59 o F (15 o C). -High rainfall &amp; mean relative humidity of 60%. High rainfall increases mosquito breeding sites and high humidity increases mosquito life-span, both of which increase the likelihood of a mosquito becoming infected and transmitting the parasite. -Anopheles spp. are found in coastal areas, lowlands, and highlands. They have been found up to about 2500 meters (8200 ft) altitude. -Females lay eggs in surface water; some species prefer open sunlit shallow seepage water, while others prefer impounded water with floating vegetation and debris. Most of the mosquitoes are found within a few kilometers of their rural breeding site. Ref: 1,2.
  3. -The massive RBC destruction and the sudden release of cell breakdown products results in the onset of fever. -Recall that there are no symptoms during the liver stages. So many RBCs can become infected, that huge numbers of them are destroyed. As this destruction occurs, severe anemia can result . -In addition, infected RBCs that aren ’ t yet destroyed develop sticky &quot;knobs&quot; on their surfaces. These knobs cause RBC clumping and sludging. RBCs adhere to capillary walls, and interfere with blood flow in vital organs such as brain, liver, lung, and kidney. Tissues become hypoxic, and tissue damage interferes with vital organ functions. -Immune complexes and mediators are released contributing to tissue hypoxia and capillary permeability. Ref: 1, 5.
  4. -Malaria can present with a non-specific prodrome lasting up to several days. Symptoms include malaise, anorexia, headache, myalgia and low grade fever. However, malaria can also start more suddenly, with acute onset of severe illness. -After several more days, the classic cyclic &quot;paroxysms&quot; may develop. These include 3 stages – cold, hot, &amp; sweating. It may take 3-7 days for the cycles to appear, if they appear at all. Until then the fevers may be erratic. -The cold stage lasts 15 minutes to several hours. Symptoms include feeling cold, shivering, and teeth chattering. Temp rises rapidly, skin is pale and cold, may see cyanosis of the lips and nail beds. -The hot stage lasts 2 to 6 hours. Fever is up to 106  F with falciparum and up to 104  F with others. Symptoms include severe headache, malaise, myalgia, anorexia, nausea and vomiting, diarrhea, dry cough, and shortness of breath; may have delirium. -The defervescence or sweating stage lasts 2 to 4 hours. The fever falls rapidly; there is profuse sweating. Afterward, the patient may be exhausted and sleep for hours, but is much improved. -After an interval free of fever the cycle of chills, fever, and sweating is repeated either daily, every other day, or every 3 rd day. -With falciparum, fevers tend to be persistent with intermittent spikes. Falciparum malaria is typically not as cyclic as the other three. But remember that these classic paroxysms often are not present, and that malaria can have ANY pattern. Ref: 1.
  5. -Patients present with a variety of symptoms depending on the stage of infection and the infecting species. Fever is virtually always present, and fever plus any other symptom might be malaria if exposure occurred. -This highlights the importance of not letting the presence of other symptoms deter you from suspecting malaria if there is a risk of exposure . Other common symptoms are chills, headache, muscle pain, abdominal pain, nausea or vomiting. -Physical findings: Temperature will almost always be increased. Pulse is rapid, may have rapid breathing. May see hypotension and diaphoresis. Skin is warm and flushed. The spleen and liver may be enlarged and tender. Confusion, cyanosis and jaundice are possible. Lymphadenopathy is NOT typically associated with malaria. Ref: 1.