Defining and Defeating the Intolerable Burden of Malaria Joel G. Breman, MD, DTPH Fogarty International Center U. S. National Institutes of Health Bio. Vision. Alexandria 2008 New Life Sciences: From Promises to Practice Alexandria, Egypt April 14, 2008
Our Goal Malaria Free Mothers and Children and all others
Defining Malaria and its Conquest l Manifestations l Burden l Goals l Interventions l Progress l Research
Transmission of Plasmodium from Mosquito to Human…to Mosquito P. falciparum P. vivax P. ovale P. malariae P. knowlsei White and Breman, 2008 (after Hoffman), Harrison’s Principles of Internal Medicine
Defining Malaria and its Conquest l Manifestations l Burden l Goals l Interventions l Progress l Research
Manifestations of the Malaria Burden Anemia Hypoglycemia Acute febrile illness Severe illness Infected Mosquito Long-term sequelae Respiratory distress Hypovolemia Death Cerebral malaria Anemia Infected Human Chronic effects Neurologic Cognitive Impaired growth and development Malnutrition Developmental Fetus Abortion, stillbirth Pregnancy Maternal Breman, Alilio, Mills, 2004, Am J Trop Med Hyg Low birth weight Acute illness Anemia Infant and fetal mortality Long-term sequelae
Overlap of Cerebral Malaria, Anemia, Respiratory Distress in Children Mali Kenya Respiratory Distress Cerebral Malaria 22/177 (12%) 31/58 (53%) 3/7 (43%) 1/14 (7%) 1/1 2/2 1/4 (100%) (25%) (100%) 3/7 3/4 (43%) (75%) 2/126 (2%) 1/2 (50%) 2/23 (9%) Severe Malarial Anemia Hypoglycemia Ranque et al 2008, Ped Inf Dis J ( ) = number of patients % = CFR Marsh et al, 1995, NEJM
Defining Malaria and its Conquest l Manifestations l Burden l Goals l Interventions l Progress l Research
Global Malaria and Endemicity, 2003
Global Distribution of Malaria Anopheline Vectors Kizewski et al. , 2004, Am J Trop Med Hyg
Plasmodium falciparum 2005 in Clinical Cases Region Africa South East Asia Population at risk (million) Cases (%) (million) 521 365 (215 - 374) (57%) 1, 314 119 (66 - 224) (34%) Western Pacific 142 15 (9 - 26) (4%) Eastern Med. 176 12 (5 - 25) (4%) 55 4 (2 - 8) (1%) 4 1 (0 - 1) (<1%) Americas Europe Total Snow et al, 2005, Nature 2, 211 515 (298 – 659) (100%)
Leading Causes of Disability-Adjusted Life Years (DALYs) in Sub-Saharan African Region, 2001 1. Total DALYs HIV/AIDS % 17. 8 2. Malaria 10. 3 3. Lower respiratory infections Perinatal conditions Diarrheal diseases Measles Tuberculosis Whooping cough Road traffic accidents Protein-energy malnutrition 8. 4 6. 3 6. 1 4. 6 2. 4 1. 9 1. 8 1. 6 4. 5. 6. 7. 8. 9. 10. Total Source: Mathers, et al. , 2006, Global Burden of Disease and Risk Factors 61. 2 Burden of Malaria on Health Systems in Sub-Saharan Africa, 1999 -2004 O U T P A T I E N T S H FE I V S E T R O R Y A D M I S S I O N S H D O E S AT P HS I T A L Source: WHO 2005
Deaths from Malaria: Children Under Five and Total, Africa 2001 Cause of malaria-related death ● Number of malaria deaths Under fives Severe anemia Hypoglycemia 153, 000 -267, 000 Low birth weight 62, 000 -363, 000 Cerebral malaria 110, 000 Respiratory distress 110, 000 Total deaths from malaria ● 190, 000 -974, 000 625, 000 -1, 824, 000 Total, all ages 962, 000 -2, 806, 000 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. vivaxand Clinical Cases Per Year (in millions) Population at risk (millions) Infections/year (millions) South East Asia 1, 347 90 -248 Western Pacific 89 20 -77 East Mediterranean 211 11 -34 Americas 78 10 -28 Europe 20 1 -4 Africa 50 — Central Asia Total Price et al, 2007, Am J Trop Med Hyg — 2, 596 — 132 -391
Surveys of P. falciparum , Eastern Mediterranean Regional Office (EMRO), 1985 -2007 Countries With Widespread Transmission, 2006 Population (millions) Afghanistan Djibouti Pakistan Somalia Sudan Yemen Total Breman and Holloway, 2007, Am J Trop Med Hyg Cases Confirmed Cases Estimated 31. 6 0. 6 164. 7 8. 8 40. 2 19. 8 265. 2 83, 000 24, 000 16, 000 589, 000 55, 000 569, 000 1, 500, 000 60, 000 1, 600, 000 1, 300, 000 5, 000 900, 000 10, 360, 000
Malaria in Eastern Mediterranean Region, WHO: Countries Having Interrupted or Limited Transmission Country Bahrain Egypt Iran Cases 70 29 15, 909 (13, 127) Country Morocco Oman Palestine Cases 83 443 2 Iraq Jordan Kuwait Lebanon Libya 24 116 (2) 235 42 10 Qator Saudi Arabia Syria Tunisia United Arab Republic Total 198 1, 278 (26) 34 36 1, 663 ( ) local transmission Breman and Holloway, 2007, Am J Trop Med Hyg 20, 142 (13, 432)
Community Surveys of P. falciparum Prevalence Conducted between 1985 and 2007 in AFRO Guerra et al, 2008, PLo. S Med MARA/ARMA (http: //www. mara. org. za)
Community Surveys of P. falciparum Prevalence Conducted between 1985 and 2007 in AMRO and SEARO-WPRO Guerra et al, 2008, PLo. S Med
Malaria Cases and Death in South East Asia Region of WHO, 2004 DEMOCRATIC PEOPLE’S REPUBLIC OF KOREA 0. 5% Malaria Cases = 2, 525, 715 Cases of Malaria in the European Region , 2005 Malaria Deaths = 3, 768 Malaria Danger in Central Asia and Kazakhstan Breman and Holloway, 2007 Am J Trop Med Hyg
Defining Malaria and its Conquest l Manifestations l Burden l Goals l Interventions l Progress l Research
Roll Back Malaria’s Goals, Strategies, and Targets To Halve the Burden of Malaria by 2010 Abuja Malaria Summit, April 2000, revised 2007 RBM strategy Abuja target (by 2005), RBM (2007) § Prompt access to effective treatment 80% patients using correct/affordable treatment w/in 24 hrs § Insecticide-treated nets (ITNs) 80% of children <5 years and pregnant women having ITNs § Prevention and control in pregnant women 80% of pregnant women using intermittent preventive treatment § Epidemics 60% detected w/in 2 weeks of onset 60% responded to w/in 2 weeks RBM, WHO, 2008
Major Manifestations of Malaria Anemia Lennart Nielson (Karolinska Instituteg), Hedvig Perlmann (Stockholm University) Martin Weber George Grau Roll Back Malaria Info Sheet Cerebral malaria Low birthweight Rick Steketee National Human Genome Research Institute
Selected Severe Patient Management Clinical Malaria Conditions Requiring Diagnosis and Reporting Condition Coma Manifestations * Required Equipment Managementa Unable to respond to stimuli Blantyre coma scale Parenteral therapy Convulsions (grand petit mal) Observation Anticonvulsants, protection from injury Renal failure Urine output in 24 h Biochemical analysis Rehydration (no overhydration) Serum creatinine Urine collections Hemofiltration if needed Febrile, hypotensive, shock (after malaria treatment) Blood culture, complete blood count Antibiotics, supportive care Rehydration, <2500 gm Scale (calibrated) Resuscitation, breast, warmth Other Sepsis * birth weight Low * Breman and Holloway, 2007, Am J Trop Med Hyg
Selected Severe Clinical Malaria Conditions Requiring Diagnosis, Assessment and Reporting (2) Condition Manifestations Hematologic Anemia * Required Equipment Managementa Hematocrit<15% Hemoglobin <50 g/d. L Hematocrit equipment Hemoglobinometer Blood transfusion Plasma glucose Analytic equipment Glucosometer Glucose infusion Arterial p. H Plasma bicarbonate Blood gas analysis Correct hypovolemia Hemofiltration >100, 000 parasites/ml Microscopy (or Rapid Diagnostic Test) Microscope, slides, reagents Parenteral treatment with artemisinins, quinine or quinidine Biochemical Hypoglycemia * Acidosis Parasitologic: Hyperparasitemia * a in addition to antimalarial drugs; referral to a secondary or temporary care facility for patients requiring parenteral therapy and intensive supportive care. b consider exchange transfusion for parasitemia >10% * essential measurement Breman and Holloway, 2007, Am J Trop Med Hyg
Defining Malaria and its Conquest l Manifestations l Burden l Goals l Interventions l Progress l Research
Control of the Malaria Burden Current Interventions Drugs (treatment, prevention) Protection (insecticideimpregnated materials) Insecticides (house spraying, larvicides) Environmental and Behavioral Modification Vaccines (preerythrocytic, blood stage, transmissionblocking) Future Interventions Genetic modification of vectors
Cost-Effectiveness of Interventions Against Malaria in Sub-Saharan Africa Intermittent preventive treatment/ pregnancy (SP) Insecticide residual spraying Artemisinin comb. therapy (resistance) Insecticide-treated bed nets Intermittent preventive treatment 0 5 10 15 20 25 30 Cost-effectiveness ratio ($ per DALY Laxminarayan et al (DCPP authors), 2006, averted) et al, Disease Control Priorities in Developing Countries, in Jamison nd ed. 2
Malaria: Prevention and Treatment n Treatment with a new group of antimalarials – the artemisinin compounds, in combination with lumefantrine, amodiaquine, sulfadoxine– pyrimethamine, or others Artemesia annua Spread of chloroquine resistance
The Process for the Microbial Production of Artemisinin WHO/Tropical Diseases Research/Crump Verband Forschender Arzneimittelhersteller e. V. Hale et al, 2007, Am J Trop Med Hyg
Insecticide Treated Materials Work Sleep Inside the Net
Anopheles Mosquito, Larva Breeding Sites
Insecticides recommended by the World Health Organization for Indoor Residual Spraying Insecticide Class DDT Organochlorine Fenitrothion Organophosphate Malathion Organophosphate Pirimiphos-methyl Organophosphate Propoxur Carbamate Bendiocarb Carbamate Alpha-cypermethrin Pyrethroid Cyfluthrin Pyrethroid Deltamethrin Pyrethroid Etofenprox Pyrethroid Lambda-cyhalothrin Pyrethroid Bifenthrin Pyrethroid *DDT, dichlorodiphenyltrichloroethane Cost/ratio $1. 6/1. 0 8. 2/5. 1 8. 6/5. 4 13. 8/8. 6 14. 8/9. 3 18. 8/11. 8 Sadasivaiah et al, 2007, Am J Trop Med Hyg 1 -2 2 2 1 -2 0. 1 -0. 4 0. 02 -0. 03 0. 02 -0. 05 0. 02 -0. 025 0. 1 -0. 3 0. 02 -0. 03 0. 025 -0. 05 Duration of effective action (months) >6 3 -6 2 -3 3 -6 2 -6 4 -6 3 -6 3 -6 3 -6 Photo: World Health Organization Cost/house/6 months DDT Deltamethrin Malathion Lambda-cyhalothrin Bendiocarb Fenitrothion Propoxur Recommended dosage of active ingredient (g/m 2)
Insecticides Used for Malaria Vector Control, 1995 -2006 Vector Surveillance Capacity in Sub-Saharan Africa, 2006 9000 8000 7000 DDT thousands of kg 6000 5000 OP 4000 C 3000 PY 2000 19 9 19 5 9 19 6 9 19 7 9 19 8 9 20 9 0 20 0 0 20 1 0 20 2 3 0 20 4 05 0 thousands of kg Entomological Capacity, 2006 no capacity basic for control or research basic/advanced for control, advanced in research WHO, 2004, Sadasavaiah, Tozan, Breman, 2007
Flamboyant Trees on the Grounds of the Lamumba Health Clinic in Kisumu, Kenya Omlin et al, 2007, Am J Trop Med
Malaria Diagnostics: Microscopy and Rapid Diagnostic Testing Blood Smears RDT
Global Fund: HIV/AIDS, Tuberculosis, and Malaria per-capita funding levels Source: UNICEF, 2007 Countries with President’s Malaria Initiative and World Bank Booster Funding
Defining Malaria and its Conquest l Manifestations l Burden l Goals l Interventions l Progress l Research
Rwanda: Malaria Progress Vital Statistics Malaria Population: 9. 3 million Risk: 4. 8 million Women 15 -45 yrs: 2. 7 million Cases: 1. 4 million (2005) Children <5 yrs: 4. 0 million Deaths <5 yrs: 510 (2006) Infant mortality: 152 (2005) Indicator 2000(%) 2005 (%) 2007 (%) — 17 60 — 0 65 Children with fever (%) receiving anti-malaria drugs 13 12 — receiving drugs <24 hours — 3 — sleeping under ITN 5 13 60 Pregnant women sleeping under ITN received IPT (≥ 2 doses) Roll Back Malaria
Ethiopia: Malaria Progress Vital Statistics Malaria Population: 77. 3 million Risk: 52. 5 million < 5 mortality: 123 Cases (est): 12 million (2006) (reported): 3. 7 million Child Deaths : 94, 400 Indicator 2005 (%) 2006 (%) % Households with ≥ 1 ITN 3 91 Children < 5 yrs sleeping under ITN previous night 2 87 Pregnant women sleeping under ITN previous night 1 — Roll Back Malaria
Vital Statistics Zambia: Malaria Progress Malaria Cases: 2. 1 million (2005) Population: 11. 7 million Indicator 2002 (%) 2004 (%) 2006 (%) % Households with ≥ 1 ITN 14 27 44 Children < 5 yrs sleeping under ITN 16 — 27 Pregnant women sleeping under ITN 8 12 24 Roll Back Malaria
Results from Zanzibar Island, Tanzania Population: 1, 116, 001 (2006)
Results from Zanzibar Outpatient Malaria Cases (Confirmed and non-confirmed) per 1000 of the population Ali, et al 2007, EARN Meeting Proportion of malaria confirmed cases
Defining Malaria and its Conquest l Manifestations l Burden l Goals l Interventions l Progress l Research
Research Needs: Disease Burden that Can or Cannot be Averted with Existing Interventions Disease Burden: Not Avertable Already averted Avertable Biomedical research to identify new and improved interventions Increase effectiveness or reduce costs of existing interventions coverage 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 Gaps and Controversies Requiring Attention n n Multiple pathologies – Anemia – Low birthweight – Malnutrition – HIV – Enteritis – Sepsis – Neurocognitive – Neglected diseases Host factors – Immunity and vaccines – Genetic susceptibility n Plasmodium – falciparum – vivax – – n Anopheles – – n Antigenic diversity Drug resistance Transmission dynamics Human Correlation of Entomologic Inoculation Rate with clinical manifestations Special conditions – Epidemics – Urbanization – Migration
Fetal Growth Velocity and Impact of Intermittent Preventive Treatment for Malaria of Mothers Rogerson 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 Mosquito Vaccine Targets White and Breman, 2007 (adapted from Hoffman), Harrison’s Principles of Internal Medicine
October 17, 2007
Thank you jbreman@nih. gov
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