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 needleOrgan transplantCongenital (<5% of newborns of infected mothers)
PathogenesisRBC destructionImmune complexes and mediatorsCapillary permeabilityTissue hypoxia
Acute SymptomsParasites 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 MalariaMost of these are attributable to P.
falciparum (90 percent), but P. vivax and P. knowlesi can also cause severe disease
Severe Falciparum MalariaAlso known as Complicated malaria or
Malignant Tertian malariaMortality rate of ~0.1% - appropriately
treated, uncomplicated falciparum malariaMortality rate >30% - multiple vital organ
dysfunctionA 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 IndiaCharacteristics 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 MalariaPresence 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 andVisitors (of any age) from non-endemic areas. Non-transmission / low-transmission areasTravelers 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 MalariaClinical 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)PathogenesisRenal 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.
AnemiaResults from
Accelerated red cell destructionRemoval by the spleenIneffective erythropoiesis.
Metabolic acidosisCauses:renal failureprimary 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 concentrationBEST 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
glycogenolysiso 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. DiagnosisMicroscopy
Thick film - presence/absenceThin film - morphology/speciesFluorescent microscopy (acridine orange)Capillary – fluorescence (QBC assay)
Other Rapid Diagnostic Tests (RDTs)Antigen capture( pfHRP2, pLDH) PCR
Microscopic diagnosisGold standardSensitivity : 5-10 parasites/μlThick smear : rapid diagnosisThin smear : species identificationOther advantages:
Platelets, toxic granules, anemia
If negative, repeat 6 times 6 hourly.
Indian pediatrics 2005
Microscopy….contd..Collection of blood sample
before administration of antimalarialsnot necessarily during fever
Examination done in 100x oil immersion using giemsa stain, minimum of 100 fields examined before concluding slide negative
Microscopy….contd..oWhy parasites not detected in peripheral
smear ?o sequestration in deep vascular bedo partially treated patientso prophylactic antimalarial treatmento inexperienced microscopisto poor quality stainingo Slide Positivity Rate lower in 1-3 yrs age group
Indian pediatrics 2005/ June 1999
Rapid Diagnostic Tests
Histidine-rich protein 2 of P. falciparumwater 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/µLSensitivity 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
antigenLancet Infect Dis 2006; 6: 582–88
Rapid Diagnostic Tests….contd..Plasmodium aldolase
Enzyme of the parasite glycolytic pathwayexpressed by the blood stages of all
Plasmodium : pan-specific: the pan malarial antigen (PMA)
Parasite lactate dehydrogenase (pLDH)glycolytic enzyme produced by live parasitesdifferent isomers of pLDH for each of the 4
species existdetect 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%
ELISAAntibodies 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 techniquesIntraleucocytic 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 spectrometrySensitivity of 10 parasites/µL of blood
Guiding factorsTreatment 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 treatmentProviding 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 + lumefantrineArtesunate 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 regionAS plus tetra/doxy/ clinda for 7 daysquinine plus tetra/doxy/ clinda for 7 days
Guidelines for the treatment of malaria. 2nd ed. WHO. 2010
Treatment of severe malariaAS: 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 malariaAfter parenteral artemisinin therapy, patients
will receive a full course of oral ACT for 3 daysThose 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
3. 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 ofuncomplicated 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 ≥ 37.5oC 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 ≥ 37.5oC (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 < 37.5oC, w/o
previously meeting any of the criteria of early treatment failure
OTHER SUPPORTIVE MEASURES
SUPPORTIVE MEASURESIf 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 cultureEmpirical antibiotic treatment
SUPPORTIVE MEASURESAnemia
Ideally fresh blood should be transfusedIn 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)ManagementCorrection of dehydrationDiuretic therapyHemodialysis 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 indicatorsHyperparasitaemia 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 glucoseRaised venous lactic acid (>5 mmol/l)More than 3-fold elevation of serum enzymes
(aminotransferases)Increased plasma 5'-nucleotidaseLow antithrombin III levelsVery 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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