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