Treatment of Severe Childhood P. Falciparum Malaria ... - iDOC Africa

Treatment of Severe ChildhoodP. Falciparum MalariaGuidelines OverviewNyokabi Musila

Outline• Definition of severe malaria in African children• Evidence reviews on treatment of severechildhood malaria• National and global guidance• Treatment of severe childhood malaria• Treatment of uncomplicated childhood malaria• Questions• Summary

Endemicity of childhood malaria in 2009

Why is endemicity important?In a recent study of ~4,500 children admitted tohospitals in northern Tanzania all with a diagnosisof ‘severe malaria’• Only half hlfof the 4,500 hd had malaria on a bloodslide• Only 1 in 5 children aged 1200m, a low risk malaria area, hadmalaria on a blood slide• Death was much more common in those• Death was much more common in thosefalsely diagnosed as malaria

Criteria useful for defining severe malaria in Africanchildren in endemic areasCerebral MalariaConvulsionsSevere anaemiaAcute renal failureXHypoglycaemiaShock ?Pulmonary oedemaXBleedingHyperpyrexiaXHyperparasitaemiaHaematuria ?XXXPlus….Respiratory distress

Other forms of severe malaria……in endemicareasAcute renalfailurePulmonaryoedemaBleedingHyperpyrexia,Temp >42 0 C• These are either souncommon in malaria, or notcaused by malaria at all inchildren in endemic areas,that you should assumeanother cause or disease ispresent.• Assuming these are caused bymalaria is very dangerous.

Life‐threatening malariaComa‘3’ group ‘2’ group ‘1’ groupRespiratorydistressHypoglycaemiayInability to sitor drinkSevereanaemiaMultipleconvulsions1 convulsionHightemperatureHigh risk ofdeathSome risk ofdeathVery Low riskof death

Life‐threatening malariaComa‘3’ group ‘2’ group ‘1’ groupRespiratorydistressHypoglycaemiaInability to sitor drinkSevereanaemiaMultipleconvulsions1 convulsionHightemperatureRespiratory distress & Severe Anaemia,3 x 2 = Very high h risk of death

Life‐threatening malaria‘3’ groupComaRespiratorydistressHypoglycaemia‘2’ groupInability to sitor drinkSevereanaemiaMultipleconvulsions‘1’ group1 convulsionHightemperature1 convulsion & hightemperature,1 x 1 = Very low risk of death

Diagnosing childhood severe malariaComain endemic areas‘3’ group ‘2’ group ‘1’ groupRespiratorydistressHypoglycaemiayInability to sitor drinkSevereanaemiaMultipleconvulsions1 convulsionHightemperature+ confirmation with+ confirmation withmicroscopy or RDTmicroscopy or RDTLife threatening:requires parenteral txNOT life threatening:manage with oral tx

Treatment of severe childhoodmalaria

Treatment of childrenwith severe malaria• Severe malaria is a medical emergency• Primary treatment objective is prevention ofdeath• Secondary treatment objective is prevention ofdisabilities and recrudescence• Chloroquine and sulphadoxine‐pyrethamine (SP)are NOT recommended• 2 classes of drugs: cinchona alkaloids (quinineand quinidine) and artemisinin derivatives

GoK GuidanceMinistry of HealthBasic Paediatric Protocols (2005)Republic of Kenya.Paediatric Protocols for District Hospitals.December 2005UPDATEBasic Paediatric Protocols (2010)National Guidelines for theDiagnosis, Treatment andPrevention of Malaria inKenya (2010)

WHO GuidanceGlobal recommendations on thecase management of malariaGRADE tool used only for newevidence of 2010 updateFramework for policy‐makers tomake more country‐specifictreatment protocols that take intoaccount local resistance patterns& health service capacity

WHO 2010: Pre‐referral treatment ofsevere childhood malaria• Rectal Artesunate 10 mg/kg*OR• IM Quinine loading dose 20 mg/kgOR• IM Artesunate 24mg/kg 2.4mg/kgOR• IM Artemether 32mg/kg 3.2 loading dose*Based on 2 African studies that show pre referral rectal artesunate*Based on 2 African studies that show pre‐referral rectal artesunate10mg/kg reduces the risk of death and permanent disability in childrenunder 5

GoK 2010: Pre‐referral treatment ofsevere childhood malariaFirst‐lineIM quinine loading dose 20 mg/kg (salt)Second‐line (in absence of quinine)• Rectal artesunate 10 mg/kgOR• IM Artesunate 2.4mg/kgOR• IM Artemether 3.2 mg/kg loading doseCheck in hospitals to avoid double loading

Primary EvidenceQuinine vs. Artemisininsderivatives

Evidence for treatment of severe malariain children with quinine – EfficacyWhat is the effectiveness of quinine compared toartemisinin derivatives in the treatment of severemalaria in African children?

POPULATION INTERVENTION CONTROL OUTCOMEChildren /newbornsQuinineArtemisininderivatives1° outcome• Mortality2° outcomes• Clinicalcuranceindicators• AdverseeventsSample size(N)IVQuinineIMartemisininderivative1258 Quinine Artemether194 Quinine β ‐Arteether72 Quinine Artesunate

Evidence SummaryQuinine vs Artemisinins for severemalaria in childrenEquivocal in• risk of death• parasite clearance time• fever clearance time• coma resolution time• incidence of neurological sequelae• 28 th day cure rateStrength ofevidenceModerateto lowquality

Africa Quinine versus Artesunate in SevereMl Malaria Trial Ti l(AQUAMAT)• Multi‐centre trial in 9 African countries• Target number of children: 5,300 patients• Anticipated end date: 31 st December 2010.

Primary EvidenceQuinineiLoading dosevs.No loading dose

Principle of quinine loading dose fortreatment of severe malariaQuin nine lev vel in bo odyTime spent withinadequate levelwithout loading doseWith loading doseLevel requiredto kill parasitesWithout loading dose0 12Days after treatment

Evidence for treatment of severe malariain children with quinine – Loading doseWhat is the effectiveness of quinine when givenwith a loading dose compared to when givenwithout a loading dose in the treatment of severemalaria in African children?

POPULATION INTERVENTION CONTROL OUTCOMEChildren /newbornsQuinine loadingdose thenmaintenancedoseNo loadingdose –uniform dose1° outcome• Mortality• Clinical curanceindicators2° outcomes• Adverse events4 African studies, n=144

Evidence summaryQuinine i loading dose vs. no loading doseLoading dose effect• Faster fever clearance• Faster parasite clearance• Increased risk of transient hearing lossStrengthofevidenceModeratequality

Evidence summaryQuinine loading dose vs. no loading doseNo difference in effect onStrength ofevidence• Risk of death• Number of convulsions• Coma recovery timeLow to• Number with asexual parasitaemia moderateafter 24 and 48 hoursquality• Neurological sequalae• Dose‐related adverse events

Malaria Treatment GuidelinesSevere childhood malaria

WHO Guidance: First‐line treatment for severechildhood malariaQuinine 20 mg/kg g (salt) loadingdose as IV infusion or divided IMinjection then 10 mg/kg g every 8hoursORArtesunate 24mg/kg 2.4 IV or IMthen at 12 hours and 24 hoursthen once daily

GoK Guidance: First‐line treatment for severechildhood malariaMinistry of HealthRepublic of Kenya.Paediatric Protocols for District Hospitals.December 20052005Quinine 15mg/kg (salt) loading doseas IV infusion i or IM injectionithen maintenance with 10 mg/kg(salt) every 12 hours until patient cantolerate oral treatment2010Quinine 20 mg/kg (salt) loading doseas IV infusion or IM injectionthen 10 mg/kg (salt) every 8 hoursuntil patient t can tolerate t oraltreatmentNEW

Quinine dosing GoK guidance2005 vs 2010• There are no efficacy studies with head‐to‐headcomparisons of the 2 dosing regimens:LD 15 mg/kg then 10 mg/kg bd(GoK 2005 regimen)vs.LD 20 mg/kg then 10 mg/kg tds(WHO 2010 / GoK 2010 regimen)• Main concern is quinine toxicity• Estimated therapeutic range of unbound quinine forKenyan strains of P Falciparum is 0.2 to 2.0 mg/l(Winstanley 1994)

WHO 2010: Second‐line treatment for severe malariaIf quinine and artesunate are notavailable, giveArtemether 3.2 mg/kg IMthen 1.6 mg/kg IM per day

GoK 2010: Second‐line treatment forsevere malariaArtesunate 24mg/kg 2.4 IV or IM loadingdosethen 1.2 mg/kg at 12 hours and 24 hoursthen once dailyORArtemether 3.2 mg/kg IM loading dosethen 1.6 mg/kg once dailyNEW

Follow‐on oral treatment forsevere childhood malaria

GoK Guidance : Follow‐on oral treatmentMinistry of Health2005 and 2010Republic of Kenya. • 1 st line:Full course of Artemetherplus lumefantrine (AL)Paediatric Protocols for District Hospitals.December 2005• 2 nd line (if AL is unavailable):Quinine every 8 hours tocomplete lt a course of 7 daysparenteral and oral treatment

WHO 2010: Follow‐on oral treatmentAfter parenteral antimalarial for aminimum of 24 hours, give one ofthe following:• Artermether plus lumefantrine (AL)• Artesunate plus amodiaquine• Dihydroartemisinin plus piperaquine pp • Artesunate plus sulphadoxinepyrethamine(SP)• Artesunate plus Clindamycin• Quinine plus Clindamycin orDoxycycline

Treatment of uncomplicatedchildhood malaria

WHO 2010: Treatment of uncomplicatedmalaria in childrenFirst‐lineOral ACTsGRADE: Moderate quality evidenceStrong recommendation

GoK 2010: Treatment of uncomplicatedmalaria in childrenRequires positive RDT/microscopy diagnosisAim: Cure of the diseaseFirst‐lineArtemether plus Lumefantrine (AL)Second line (if treatment failure)Dihydroartemisinin plus PiperaquineTreatment failure is defined as the failure to achievethe desired therapeutic response after the initiationof therapy

Differences between new GoK and WHOguidelines on treatment of severe childhoodmalariaGoK (2010) WHO (2010)• Quinine is first‐linetreatment• Limited it oral follow‐uptreatments to quinine or AL• Artesunate is interchangablewith quinine• Artemether is recommended2 nd line only if quinine andartesunate are unavailable• Specifies 24 hours minimumiparenteral treatment

Questions ?

Summary – diagnosis of childhoodsevere malaria• In malaria endemic areas severe malaria hasbeen re‐defined as one or a combination of:– Coma & neurological impairment– Respiratory distress– Hypoglycaemia– Severe anaemia• If a child has more than one feature of severemalaria it is a medical emergency.

Summary –treatment of childhoodsevere malaria• New imminent i tGoK K(2010) guidelines haveadopted:– WHO dosing recommendations for IMquinine 20mg/kg then 10mg/kg tds• Need to look at Kenyan/African evidence‐baseto inform treatment of severe malaria inKenyan children