Defining and Defeating the Intolerable Burden of Malaria

Defining and Defeating the Intolerable Defining and Defeating the Intolerable Burden of MalariaBurden of Malaria

Joel G. Breman, MD, DTPHJoel G. Breman, MD, DTPH

Fogarty International CenterFogarty International Center

U.S. National Institutes of HealthU.S. National Institutes of Health

BioVisionAlexandria 2008BioVisionAlexandria 2008

New Life Sciences: From Promises to PracticeNew Life Sciences: From Promises to Practice

Alexandria, EgyptAlexandria, Egypt

April 14, 2008April 14, 2008

Our Goal Malaria Free Mothers and Malaria Free Mothers and

ChildrenChildren

and all others

Defining Malaria and its ConquestDefining Malaria and its Conquest

Manifestations

Burden

Goals

Interventions

Progress

Research

Transmission of Transmission of PlasmodiumPlasmodium from from Mosquito to Human…to MosquitoMosquito to Human…to Mosquito

White and Breman, 2008 (after Hoffman), Harrison’s Principles of Internal Medicine

P. falciparum

P. vivax

P. ovale

P. malariae

P. knowlsei


ManifestationsBurden

Goals

Interventions

Progress

Research

Manifestations of the Malaria BurdenManifestations of the Malaria Burden

Infected Mosquito

Infected Human

Chronic effects

Anemia

Neurologic

Cognitive

Developmental

Impaired growth and development

Malnutrition

Acute febrile illness

Severe illness

Anemia

Hypoglycemia

Cerebral malaria

DeathRespiratory distress

Pregnancy

Fetus

MaternalAcute illness

Anemia

Low birth weight

Abortion, stillbirth

Infant and fetal mortality

Long-termsequelae

Hypovolemia

Long-termsequelaeBreman, Alilio, Mills, 2004, Am J Trop Med Hyg

Overlap of Cerebral Malaria, Anemia, Respiratory Distress in Children

Marsh et al, 1995, NEJM

Respiratory Distress

Severe Malarial Anemia

Hypoglycemia

Cerebral Malaria

22/177(12%)

3/7(43%)

2/126(2%)

1/14(7%)

1/4(25%)

2/2(100%)

1/1(100%)

3/7(43%)

3/4(75%)

1/2(50%)

2/23(9%)

Ranque et al 2008, Ped Inf Dis J( ) = number of patients

31/58(53%)

KenyaMali

% = CFR


Manifestations

BurdenGoals

Interventions

Progress

Research

Global Malaria and Endemicity, Global Malaria and Endemicity, 20032003

Global Distribution of Malaria Global Distribution of Malaria Anopheline VectorsAnopheline Vectors

Kizewski et al., 2004, Am J Trop Med Hyg

Plasmodium falciparum in 2005

Clinical CasesRegionRegion Population Population

at riskat risk (million)(million)

Cases (%)Cases (%)

((million)million)

AfricaAfrica 521521 365 (215 - 374) 365 (215 - 374) (57%)(57%)

South East South East AsiaAsia

1,3141,314 119 (66 - 224) 119 (66 - 224) (34%)(34%)

Western Western PacificPacific

142142 15 (9 - 26) (4%)15 (9 - 26) (4%)

Eastern Med.Eastern Med. 176176 12 (5 - 25) (4%)12 (5 - 25) (4%)

AmericasAmericas 5555 4 (2 - 8) (1%)4 (2 - 8) (1%)

EuropeEurope 44 1 (0 - 1) (<1%)1 (0 - 1) (<1%)

Total 2,211 515 (298 – 659) (100%)

Snow et al, 2005, Nature

Leading Causes of Disability-Leading Causes of Disability-Adjusted Life Years (DALYs) Adjusted Life Years (DALYs)

in Sub-Saharan African in Sub-Saharan African Region, 2001Region, 2001

Total DALYsTotal DALYs %%

1.1. HIV/AIDSHIV/AIDS 17.817.8

2.2. MalariaMalaria 10.310.3

3.3. Lower respiratory infections Lower respiratory infections 8.4 8.4

4.4. Perinatal conditionsPerinatal conditions 6.3 6.3

5.5. Diarrheal diseasesDiarrheal diseases 6.1 6.1

6.6. MeaslesMeasles 4.6 4.6

7.7. TuberculosisTuberculosis 2.4 2.4

8.8. Whooping coughWhooping cough 1.9 1.9

9.9. Road traffic accidentsRoad traffic accidents 1.8 1.8

10.10. Protein-energy malnutritionProtein-energy malnutrition 1.6 1.6

TotalTotal 61.261.2

Source: Mathers, et al., 2006, Global Burden of Disease and Risk Factors

Burden of Malaria on Health Burden of Malaria on Health Systems in Sub-Saharan Africa, Systems in Sub-Saharan Africa,

1999-20041999-2004

Source: WHO 2005

OUTPATIENTS

FEVER

HISTORY

ADMISSIONS

HOSPITAL

DEATHS

Number of malaria deathsCause of malaria-related death

Severe anemia 190,000-974,000

Hypoglycemia 153,000-267,000

Low birth weight 62,000-363,000

Cerebral malaria 110,000

Respiratory distress 110,000

Total deaths from malaria 625,000-1,824,000

Deaths from Malaria: Children Deaths from Malaria: Children Under FiveUnder Five

and Total, Africa 2001and Total, Africa 2001

962,000-2,806,000

● 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 Population at Risk of P. vivax P. vivax and and Clinical Cases Per Year (in millions)Clinical Cases Per Year (in millions)

Price et al, 2007, Am J Trop Med Hyg

Population at Population at risk (millions)risk (millions)

Infections/year Infections/year (millions)(millions)

South East AsiaSouth East Asia 1,3471,347 90-24890-248

Western PacificWestern Pacific 8989 20-7720-77

East East MediterraneanMediterranean

211211 11-3411-34

AmericasAmericas 7878 10-2810-28

EuropeEurope 2020 1-41-4

AfricaAfrica 5050 ——

Central AsiaCentral Asia — — ——

TotalTotal 2,5962,596 132-391132-391

Countries With Widespread Transmission, 2006

Breman and Holloway, 2007, Am J Trop Med Hyg

PopulatioPopulatio

n n (millions)(millions)

Cases Cases ConfirmeConfirme

dd

Cases Cases EstimatEstimat

eded

AfghanistaAfghanistann

31.631.6 83,00083,000 1,500,01,500,00000

DjiboutiDjibouti 0.60.6 2,0002,000 60,00060,000

PakistanPakistan 164.7164.7 24,00024,000 1,600,01,600,00000

SomaliaSomalia 8.88.8 16,00016,000 1,300,01,300,00000

SudanSudan 40.240.2 589,000589,000

5,000,05,000,00000

YemenYemen 19.819.8 55,00055,000 900,000900,000

TotalTotal 265.2265.2 569,000569,000 10,360,10,360,000000

Surveys of Surveys of P. falciparumP. falciparum, Eastern , Eastern Mediterranean Mediterranean

Regional Office (EMRO), 1985-2007Regional Office (EMRO), 1985-2007

Malaria in Eastern Mediterranean Region, WHO:

Countries Having Interrupted or Limited Transmission


CountryCountry CasesCases CountryCountry CasesCases

BahrainBahrain 7070 MoroccoMorocco 8383

EgyptEgypt 2929 OmanOman 443443

IranIran 15,909 15,909 (13,127)(13,127)

PalestinePalestine 22

IraqIraq 2424 QatorQator 198198

JordanJordan 116 (2)116 (2) Saudi Saudi ArabiaArabia

1,278 (26)1,278 (26)

KuwaitKuwait 235235 SyriaSyria 3434

LebanonLebanon 4242 TunisiaTunisia 3636

LibyaLibya 1010 United United Arab Arab RepublicRepublic

1,6631,663

TotalTotal 20,142 20,142 (13,432)(13,432)

( ) local transmission

Community Surveys of Community Surveys of P. falciparumP. falciparum Prevalence Conducted between 1985 Prevalence Conducted between 1985

and 2007 in AFROand 2007 in AFRO

Guerra et al, 2008, PLoS Med MARA/ARMA (http://www.mara.org.za)

Community Surveys of Community Surveys of P. falciparumP. falciparum Prevalence Conducted between 1985 and Prevalence Conducted between 1985 and

2007 2007 in AMRO and SEARO-WPROin AMRO and SEARO-WPRO

Guerra et al, 2008, PLoS Med

Malaria Cases and Death in South East Asia Region Malaria Cases and Death in South East Asia Region of WHO, 2004of WHO, 2004

Malaria Cases = 2,525,715

DEMOCRATIC PEOPLE’S REPUBLIC OF KOREA

0.5%

Malaria Deaths = 3,768Malaria Danger in Central Asia and Malaria Danger in Central Asia and Kazakhstan

Breman and Holloway, 2007Am J Trop Med Hyg

Cases of Malaria in the European Cases of Malaria in the European Region , 2005Region , 2005


Manifestations

Burden

GoalsInterventions

Progress

Research

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

RBM strategy

Prompt access to effective treatment

Insecticide-treated nets (ITNs)

Prevention and Prevention and control in pregnant control in pregnant womenwomen

Epidemics

Abuja target (by 2005), RBM (2007)

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

80% of children <5 years and pregnant women having ITNs

80% of pregnant women using 80% of pregnant women using intermittent preventive intermittent preventive treatmenttreatment

60% detected w/in 2 weeks of 60% detected w/in 2 weeks of onsetonset

60% responded to w/in 2 weeks60% responded to w/in 2 weeks

Roll Back Malaria’s Goals, Strategies, Roll Back Malaria’s Goals, Strategies, and Targetsand Targets

RBM, WHO, 2008

Major Manifestations of MalariaMajor Manifestations of Malaria

Cerebral malaria

Anemia

Martin WeberLennart Nielson (Karolinska Instituteg), Hedvig Perlmann (Stockholm University)

George Grau Roll Back Malaria Info Sheet

Rick Steketee National Human Genome Research Institute

Low birthweight

ConditionCondition ManifestationsManifestations Required EquipmentRequired Equipment ManagementManagementaa

ComaComa

Unable to respond to stimuliUnable to respond to stimuli Blantyre coma scaleBlantyre coma scale Parenteral therapyParenteral therapy

ConvulsionsConvulsions Convulsions (grand and Convulsions (grand and

petit mal)petit mal)

ObservationObservation Anticonvulsants, Anticonvulsants, protection from injuryprotection from injury

Renal failureRenal failure Urine output in 24h Urine output in 24h

Serum creatinineSerum creatinine

Biochemical analysisBiochemical analysis

Urine collectionsUrine collections

Rehydration (no Rehydration (no overhydration)overhydration)

Hemofiltration if Hemofiltration if neededneeded

Other Other

SepsisSepsis

Febrile, hypotensive, shock Febrile, hypotensive, shock (after malaria treatment)(after malaria treatment)

Blood culture, complete Blood culture, complete blood countblood count

Antibiotics, supportive Antibiotics, supportive carecare

Rehydration, Rehydration,

Low birth weightLow birth weight <2500 gm<2500 gm Scale (calibrated)Scale (calibrated) Resuscitation, breast, Resuscitation, breast, warmthwarmth

Selected Severe Patient Management Clinical Malaria Conditions Selected Severe Patient Management Clinical Malaria Conditions Requiring Diagnosis and ReportingRequiring Diagnosis and Reporting


*

*

*

ConditionCondition ManifestationsManifestations Required EquipmentRequired Equipment ManagementManagementaa

HematologicHematologic

Anemia Anemia Hematocrit<15%Hematocrit<15%

Hemoglobin <50 g/dL Hemoglobin <50 g/dL

Hematocrit equipmentHematocrit equipment

HemoglobinometerHemoglobinometer

Blood transfusionBlood transfusion

BiochemicalBiochemical

HypoglycemiaHypoglycemia

AcidosisAcidosis

Plasma glucosePlasma glucose

Arterial pH Arterial pH Plasma bicarbonatePlasma bicarbonate

Analytic equipmentAnalytic equipment

GlucosometerGlucosometer

Blood gas analysisBlood gas analysis

Glucose infusionGlucose infusion

Correct hypovolemiaCorrect hypovolemia

HemofiltrationHemofiltration

Parasitologic:Parasitologic:

HyperparasitemiaHyperparasitemia

>100,000 parasites/ml>100,000 parasites/ml Microscopy (or Rapid Microscopy (or Rapid Diagnostic Test)Diagnostic Test)

Microscope, slides, Microscope, slides, reagents reagents

Parenteral treatment Parenteral treatment with artemisinins, with artemisinins, quinine or quinidinequinine or quinidine

Selected Severe Clinical Malaria Conditions Requiring Diagnosis, Selected Severe Clinical Malaria Conditions Requiring Diagnosis, Assessment and Reporting (2)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 measurement


*

*

*


Manifestations

Burden

Goals

InterventionsProgress

Research

Environmental and Behavioral

Modification

Genetic modification

of vectorsFuture Interventions

Vaccines (preerythrocytic,

blood stage, transmission-

blocking)

Protection (insecticide-impregnated

materials)

Control of the Malaria Burden

Current Interventions

Drugs (treatment, prevention)

Insecticides (house

spraying, larvicides)

0 5 10 15 20 25 30

Intermittent preventive treatment

Insecticide-treated bed nets

Insecticide residual spraying

Intermittent preventive treatment/

pregnancy (SP)

Cost-effectiveness ratio ($ per DALY averted)

Cost-Effectiveness of Interventions Cost-Effectiveness of Interventions Against Malaria in Sub-Saharan AfricaAgainst 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 Malaria: Prevention and TreatmentTreatment

Treatment with a new group of Treatment with a new group of antimalarials – the artemisinin antimalarials – the artemisinin compounds, in combination with compounds, in combination with lumefantrine, amodiaquine, sulfadoxine–lumefantrine, amodiaquine, sulfadoxine–pyrimethamine, or otherspyrimethamine, or others

O

O

O O

O

Spread of chloroquine resistanceArtemesia annua

The Process for the Microbial Production of The Process for the Microbial Production of Artemisinin Artemisinin

Hale et al, 2007, Am J Trop Med Hyg

WHO/Tropical Diseases Research/Crump

Verband Forschender Arzneimittelhersteller e.V.

Insecticide Treated Materials WorkInsecticide Treated Materials Work

Sleep Inside the NetSleep Inside the Net

AnophelesAnopheles Mosquito, Larva Mosquito, Larva Breeding SitesBreeding Sites

Insecticides recommended by the World Health Insecticides recommended by the World Health Organization Organization

for Indoor Residual Sprayingfor Indoor Residual Spraying

Sadasivaiah et al, 2007, Am J Trop Med Hyg

Insecticide Class

Recommendeddosage of activeingredient (g/m2)

Duration of effective action (months)

DDTFenitrothionMalathionPirimiphos-methylPropoxurBendiocarbAlpha-cypermethrinCyfluthrinDeltamethrinEtofenprox Lambda-cyhalothrinBifenthrin

OrganochlorineOrganophosphateOrganophosphateOrganophosphateCarbamateCarbamatePyrethroidPyrethroidPyrethroidPyrethroidPyrethroidPyrethroid

1-2221-21-20.1-0.40.02-0.030.02-0.050.02-0.0250.1-0.30.02-0.030.025-0.05

>63-62-32-33-62-64-63-63-63-63-63-6

*DDT, dichlorodiphenyltrichloroethane

Photo: W

orld Health O

rganization

Cost/house/6 months

DDT

Deltamethrin

Malathion

Lambda-cyhalothrin

Bendiocarb

Fenitrothion

Propoxur

Cost/ratio

$1.6/1.0

1.6/1.0

8.2/5.1

8.6/5.4

13.8/8.6

14.8/9.3

18.8/11.8

WHO, 2004, Sadasavaiah, Tozan, Breman, 2007

Insecticides Used for Malaria Vector Control, 1995-Insecticides Used for Malaria Vector Control, 1995-2006 2006

Vector Surveillance Capacity in Sub-Saharan Africa, Vector Surveillance Capacity in Sub-Saharan Africa, 2006 2006

Entomological Capacity, 2006

no capacity

basic for control or research

basic/advanced for control, advanced in research

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

1995

1996

1997

1998

1999

2000

2001

200220

0

320

0420

05

thousands of kg

tho

usa

nd

s o

f kg

DDT

OP

C

PY

Flamboyant Trees on the Grounds of the Flamboyant Trees on the Grounds of the Lamumba Health Clinic in Kisumu, Lamumba Health Clinic in Kisumu,

KenyaKenya

Omlin et al, 2007, Am J Trop Med

Malaria Diagnostics: Microscopy and Malaria Diagnostics: Microscopy and Rapid Diagnostic TestingRapid Diagnostic Testing

Blood Smears

RDT

Source: UNICEF, 2007

Global Fund: HIV/AIDS, Global Fund: HIV/AIDS, Tuberculosis, and Malaria Tuberculosis, and Malaria per-capita funding levelsper-capita funding levels

Countries with Countries with President’s Malaria Initiative and President’s Malaria Initiative and

World Bank Booster FundingWorld Bank Booster Funding


Manifestations

Burden

Goals

Interventions

ProgressResearch

Rwanda: Malaria ProgressRwanda: Malaria Progress

Vital Statistics

Population: 9.3 million

Women 15-45 yrs: 2.7 million

Children <5 yrs: 4.0 million

Infant mortality: 152 (2005)

Malaria

Risk: 4.8 million

Cases: 1.4 million (2005)

Deaths <5yrs: 510 (2006)

IndicatorIndicator 2000(%)2000(%) 2005 (%)2005 (%) 2007 (%)2007 (%)

Pregnant womenPregnant women

sleeping under ITNsleeping under ITN —— 1717 6060

received IPT (received IPT (≥2 doses)≥2 doses) —— 00 6565

Children with fever (%)Children with fever (%)

receiving anti-malaria drugsreceiving anti-malaria drugs 1313 1212 ——

receiving drugs <24 hoursreceiving drugs <24 hours —— 33 ——

sleeping under ITNsleeping under ITN 55 1313 6060Roll Back Malaria

Ethiopia: Malaria ProgressEthiopia: Malaria ProgressVital Statistics


< 5 mortality: 123

Malaria

Risk: 52.5 million

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

Child Deaths : 94,400

IndicatorIndicator 2005 (%)2005 (%) 2006 (%)2006 (%)

% Households with % Households with ≥1 ITN≥1 ITN 33 9191

Children < 5 yrs sleeping under ITN previous nightChildren < 5 yrs sleeping under ITN previous night 22 8787

Pregnant women sleeping under ITN Pregnant women sleeping under ITN

previous nightprevious night

11 ——

Roll Back Malaria

Zambia: Malaria ProgressZambia: Malaria ProgressVital Statistics


Malaria

Cases: 2.1 million (2005)

IndicatorIndicator 2002 2002 (%)(%)

2004 2004 (%)(%)

2006 2006 (%)(%)

% Households % Households with with ≥1 ITN≥1 ITN

1414 2727 4444

Children < 5 yrs Children < 5 yrs sleeping under sleeping under ITNITN

1616 —— 2727

Pregnant women Pregnant women sleeping under sleeping under ITN ITN

88 1212 2424

Roll Back Malaria

Results from Zanzibar Results from Zanzibar Island, TanzaniaIsland, Tanzania

Population: 1,116,001 (2006)

Outpatient Malaria Cases (Confirmed and non-confirmed)

per 1000 of the population

Results from ZanzibarResults from ZanzibarProportion of malaria Proportion of malaria

confirmed casesconfirmed cases

Ali, et al 2007, EARN Meeting


Manifestations

Burden

Goals

Interventions

Progress

Research

Research Needs: Disease Burden that Can or Cannot be Averted with Existing Interventions

Not Avertable

Disease Burden:

Avertable

Already averted

coverage

Biomedical research to identify new and improved interventions

Increase 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 understanding• Fundamental research • Basic epidemiology, risk factors, modeling

New and improved tools • Drugs• Vaccines • Diagnostics• Devices• Vector control • Environmental modification• Behavioral, 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 Malaria Research Needs: Major Gaps and Controversies Requiring Gaps and Controversies Requiring

AttentionAttention Multiple pathologiesMultiple pathologies

– AnemiaAnemia– Low birthweightLow birthweight– MalnutritionMalnutrition– HIVHIV– EnteritisEnteritis– Sepsis Sepsis – NeurocognitiveNeurocognitive– Neglected diseasesNeglected diseases

Host factorsHost factors– Immunity and Immunity and

vaccinesvaccines– Genetic susceptibilityGenetic susceptibility

PlasmodiumPlasmodium– falciparumfalciparum– vivaxvivax– Antigenic diversityAntigenic diversity– Drug resistanceDrug resistance

AnophelesAnopheles– Transmission dynamicsTransmission dynamics– Human Correlation of Human Correlation of

Entomologic Entomologic Inoculation Rate with Inoculation Rate with clinical manifestationsclinical manifestations

Special conditionsSpecial conditions– EpidemicsEpidemics– UrbanizationUrbanization– MigrationMigration

Fetal Growth Velocity and Impact of Fetal Growth Velocity and Impact of Intermittent Preventive Treatment for Intermittent Preventive Treatment for

Malaria of MothersMalaria of Mothers

Rogerson et al, 2007

Overlapping Burden of Neglected Diseases Overlapping Burden of Neglected Diseases and Malariaand Malaria

(leprosy, lymphatic filariasis, onchocerciasis, (leprosy, lymphatic filariasis, onchocerciasis, schistosomiasis, schistosomiasis,

soil-transmitted helminths and trachoma)soil-transmitted helminths and trachoma)

Neglected Tropical Diseases, 2007

Malaria Transmission to Human and Malaria Transmission to Human and MosquitoMosquito

Vaccine TargetsVaccine Targets

White and Breman, 2007 (adapted from Hoffman), Harrison’s Principles of Internal Medicine

October 17, 2007

Thank youThank you

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Documents

Defining and Defeating the Intolerable Burden of Malaria