Defining and Defeating the Intolerable Burden of MalariaJoel G. Breman, MD, DTPHFogarty International CenterU.S. National Institutes of Health

BioVisionAlexandria 2008New Life Sciences: From Promises to PracticeAlexandria, Egypt

April 14, 2008

Our Goal Malaria Free Mothers and Childrenand all others

Defining Malaria and its ConquestManifestations

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Transmission of Plasmodium from Mosquito to Humanto MosquitoWhite and Breman, 2008 (after Hoffman), Harrisons Principles of Internal MedicineP. falciparum

P. vivax

P. ovale

P. malariae

P. knowlsei

Defining Malaria and its ConquestManifestations

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Manifestations of the Malaria BurdenInfected MosquitoInfected HumanChronic effectsAnemiaNeurologicCognitiveDevelopmentalImpaired growth and developmentMalnutritionAcute febrile illnessSevere illnessAnemiaHypoglycemiaCerebral malariaDeathRespiratory distressPregnancyFetusMaternalAcute illnessAnemiaLow birth weight

Abortion, stillbirthInfant and fetal mortalityLong-termsequelaeHypovolemiaLong-termsequelaeBreman, Alilio, Mills, 2004, Am J Trop Med Hyg

Overlap of Cerebral Malaria, Anemia, Respiratory Distress in ChildrenMarsh et al, 1995, NEJM Ranque et al 2008, Ped Inf Dis J( ) = number of patients31/58(53%)KenyaMali% = CFR

Defining Malaria and its ConquestManifestations

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Global Malaria and Endemicity, 2003

Global Distribution of Malaria Anopheline VectorsKizewski et al., 2004, Am J Trop Med Hyg

Plasmodium falciparum in 2005Clinical CasesSnow et al, 2005, Nature

Leading Causes of Disability-Adjusted Life Years (DALYs) in Sub-Saharan African Region, 2001Total DALYs %HIV/AIDS 17.8Malaria 10.3Lower respiratory infections 8.4 Perinatal conditions 6.3Diarrheal diseases 6.1Measles 4.6Tuberculosis 2.4Whooping cough 1.9Road traffic accidents 1.8Protein-energy malnutrition 1.6

Total 61.2

Source: Mathers, et al., 2006, Global Burden of Disease and Risk FactorsBurden of Malaria on Health Systems in Sub-Saharan Africa, 1999-2004Source: WHO 2005OUTPATIENTSFEVERHISTORYADMISSIONSHOSPITALDEATHS

Deaths from Malaria: Children Under Fiveand Total, Africa 2001Number of malaria deathsCause of malaria-related deathSevere anemia 190,000-974,000Hypoglycemia153,000-267,000Low birth weight62,000-363,000Cerebral malaria110,000Respiratory distress110,000Total deaths from malaria625,000-1,824,000962,000-2,806,000 Under fives Total, all ages

Sources Breman, Alilio and Mills, 2004, Am J Trop Med Hyg; Murphy and Breman, 2001, Am J Trop Med Hyg

Population at Risk of P. vivax and Clinical Cases Per Year (in millions)Price et al, 2007, Am J Trop Med Hyg

Countries With Widespread Transmission, 2006Breman and Holloway, 2007, Am J Trop Med HygSurveys of P. falciparum, Eastern Mediterranean Regional Office (EMRO), 1985-2007

Malaria in Eastern Mediterranean Region, WHO:

Countries Having Interrupted or Limited TransmissionBreman and Holloway, 2007, Am J Trop Med Hyg( ) local transmission

Community Surveys of P. falciparum Prevalence Conducted between 1985 and 2007 in AFROGuerra et al, 2008, PLoS MedMARA/ARMA (http://www.mara.org.za)

Community Surveys of P. falciparum Prevalence Conducted between 1985 and 2007 in AMRO and SEARO-WPROGuerra et al, 2008, PLoS Med

Malaria Cases and Death in South East Asia Region of WHO, 2004Malaria Cases = 2,525,715DEMOCRATIC PEOPLES REPUBLIC OF KOREA0.5%Malaria Deaths = 3,768Malaria Danger in Central Asia and KazakhstanBreman and Holloway, 2007Am J Trop Med HygCases of Malaria in the European Region , 2005

Defining Malaria and its ConquestManifestations

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To Halve the Burden of Malaria by 2010Abuja Malaria Summit, April 2000, revised 2007RBM strategy

Prompt access to effective treatment

Insecticide-treated nets (ITNs)

Prevention and control in pregnant women

Epidemics

Abuja target (by 2005), RBM (2007)

80% patients using correct/affordable treatment w/in 24 hrs

80% of children

Major Manifestations of MalariaCerebral malariaAnemiaMartin WeberLennart Nielson (Karolinska Instituteg), Hedvig Perlmann (Stockholm University)George GrauRoll Back Malaria Info SheetRick SteketeeNational Human Genome Research InstituteLow birthweight

Selected Severe Patient Management Clinical Malaria Conditions Requiring Diagnosis and ReportingBreman and Holloway, 2007, Am J Trop Med Hyg***

ConditionManifestationsRequired EquipmentManagementaComa Unable to respond to stimuliBlantyre coma scaleParenteral therapyConvulsionsConvulsions (grand and petit mal)ObservationAnticonvulsants, protection from injury Renal failureUrine output in 24h

Serum creatinineBiochemical analysis

Urine collectionsRehydration (no overhydration)

Hemofiltration if needed

Other Sepsis

Febrile, hypotensive, shock (after malaria treatment)Blood culture, complete blood count

Antibiotics, supportive careRehydration,

Low birth weight

Selected Severe Clinical Malaria Conditions Requiring Diagnosis, Assessment and Reporting (2)a in addition to antimalarial drugs; referral to a secondary or temporary care facility for patients requiring parenteraltherapy and intensive supportive care.b consider exchange transfusion for parasitemia >10%* essential measurementBreman and Holloway, 2007, Am J Trop Med Hyg***

ConditionManifestationsRequired EquipmentManagementa Hematologic Anemia Hematocrit

Defining Malaria and its ConquestManifestations

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051015202530Intermittent preventive treatmentInsecticide-treated bed netsInsecticide residual sprayingIntermittent preventive treatment/ pregnancy (SP)Cost-effectiveness ratio ($ per DALY averted)Cost-Effectiveness of Interventions Against Malaria in Sub-Saharan Africa

Laxminarayan et al (DCPP authors), 2006, in Jamison et al, Disease Control Priorities in Developing Countries, 2nd ed.Artemisinin comb.therapy (resistance)

Malaria: Prevention and Treatment

Treatment with a new group of antimalarials the artemisinin compounds, in combination with lumefantrine, amodiaquine, sulfadoxinepyrimethamine, or others

Spread of chloroquine resistanceArtemesia annua

The Process for the Microbial Production of Artemisinin Hale et al, 2007, Am J Trop Med HygWHO/Tropical Diseases Research/CrumpVerband Forschender Arzneimittelhersteller e.V.

Insecticide Treated Materials WorkSleep Inside the Net

Anopheles Mosquito, Larva Breeding Sites

Insecticides recommended by the World Health Organization for Indoor Residual SprayingSadasivaiah et al, 2007, Am J Trop Med Hyg*DDT, dichlorodiphenyltrichloroethanePhoto: World Health Organization

Cost/house/6 monthsDDTDeltamethrinMalathionLambda-cyhalothrinBendiocarbFenitrothionPropoxurCost/ratio$1.6/1.0 1.6/1.0 8.2/5.1 8.6/5.413.8/8.614.8/9.318.8/11.8

Insecticides Used for Malaria Vector Control, 1995-2006 Vector Surveillance Capacity in Sub-Saharan Africa, 2006

WHO, 2004, Sadasavaiah, Tozan, Breman, 2007 Entomological Capacity, 2006no capacitybasic for control or researchbasic/advanced for control, advanced in research

Flamboyant Trees on the Grounds of the Lamumba Health Clinic in Kisumu, KenyaOmlin et al, 2007, Am J Trop Med

Malaria Diagnostics: Microscopy and Rapid Diagnostic TestingBlood SmearsRDT

Source: UNICEF, 2007Global Fund: HIV/AIDS, Tuberculosis, and Malaria per-capita funding levelsCountries with Presidents Malaria Initiative and World Bank Booster Funding

Defining Malaria and its ConquestManifestations

Burden

Goals

Interventions

Progress

Research

Rwanda: Malaria ProgressVital Statistics

Population: 9.3 million

Women 15-45 yrs: 2.7 million

Children

Ethiopia: Malaria ProgressVital Statistics

Population: 77.3 million

< 5 mortality: 123

Malaria

Risk: 52.5 million

Cases (est): 12 million (2006) (reported): 3.7 million

Child Deaths : 94,400

Roll Back Malaria

Zambia: Malaria ProgressVital Statistics

Population: 11.7 million

Malaria

Cases: 2.1 million (2005)

Roll Back Malaria

Results from Zanzibar Island, TanzaniaPopulation: 1,116,001 (2006)

Outpatient Malaria Cases (Confirmed and non-confirmed) per 1000 of the populationResults from ZanzibarProportion of malaria confirmed casesAli, et al 2007, EARN Meeting

Defining Malaria and its ConquestManifestations

Burden

Goals

Interventions

Progress

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Research Needs: Disease Burden that Can or Cannot be Averted with Existing InterventionsNot AvertableDisease Burden:AvertableAlready avertedcoverageBiomedical research to identify new and improved interventionsIncrease effectiveness or reduce costs of existing interventions

Broader implementation of cost-effective interventions; identify obstacles to expansion of coverage

Research and Development Categories and Results for Implementation New basic understandingFundamental research Basic epidemiology, risk factors, modeling

New and improved tools DrugsVaccines DiagnosticsDevicesVector control Environmental modificationBehavioral, social, and economic change

Research and Development Categories and Results for Implementation New and improved intervention methods Treatment algorithms and guidelines Intervention packaging Priority setting via costing and cost-effectiveness studies Delivery: health systems and health services New and improved policy instruments

Malaria Research Needs: Major Gaps and Controversies Requiring AttentionMultiple pathologiesAnemiaLow birthweightMalnutritionHIVEnteritisSepsis NeurocognitiveNeglected diseases

Host factorsImmunity and vaccinesGenetic susceptibility

PlasmodiumfalciparumvivaxAntigenic diversityDrug resistance

AnophelesTransmission dynamicsHuman Correlation of Entomologic Inoculation Rate with clinical manifestations

Special conditionsEpidemicsUrbanizationMigration

Fetal Growth Velocity and Impact of Intermittent Preventive Treatment for Malaria of MothersRogerson et al, 2007

Overlapping Burden of Neglected Diseases and Malaria(leprosy, lymphatic filariasis, onchocerciasis, schistosomiasis, soil-transmitted helminths and trachoma)Neglected Tropical Diseases, 2007

Malaria Transmission to Human and MosquitoVaccine TargetsWhite and Breman, 2007 (adapted from Hoffman), Harrisons Principles of Internal Medicine

October 17, 2007

Thank youjbreman@nih.gov