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Bad Air

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Bad Air

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  1. Bad Air Thomas Holland October 25, 2007

  2. “What is the most repeated failure in all of global health? It could well be the commitment to eradicate malaria.” Bill Gates, October 17,2007

  3. 45 minutes from now you will know all of this: • Malaria epidemiology • A historical perspective on malaria • Some romantic malaria-themed poetry to use on your next date • Clinical manifestations and diagnosis • Basics of treatment • Malaria at DUMC • Global eradication efforts • Why the VA Jets will win the Turkey Bowl this year

  4. What is malaria? • Malaria is a vector-borne disease caused by protozoa: • P. falciparum • P. vivax • P. ovale • P. malariae • P. knowlesi

  5. Worldwide Distribution SI Hay, CA Guerra, AJ Tatem, AM Noor and RW Snow, The global distribution and population at risk of malaria: past, present and future, Lancet Infect Dis4 (2004), pp. 327–336.

  6. Worldwide distribution

  7. Malaria Epidemiology • 300-500 million cases per year worldwide • 700,000 to 2.7 million deaths per year • ~1300 cases in the US reported to the CDC in 2004 • Average 2 cases per year at DUMC

  8. Malaria in Antiquity • Genetic analysis has suggested that a virulent Plasmodia falciparum evolved 6000 years ago (“Malaria’s Eve”) around the time of the emergence of agricultural societies • However it appears that some populations are 50,000 to 400,000 years old  ie, older than homo sapiens  

  9. Malaria in antiquity • Enlarged spleen, periodic fevers, headaches, and chills are described in the Ebers papyrus (~1550 BC) as well as in ancient Chinese medical texts

  10. Nobel Prizes for work on malaria • 1902 – Ronald Ross • 1907 – Charles Louis Alphonse Laveran • discovered that malaria is caused by a protozoan • 1927 – Julius Wagner-Juaregg • for his discovery of the therapeutic value of malaria inoculation in the treatment of dementia paralytica (caused by neurosyphilis) • 1948 - Paul Hermann Müller • For his discovery of the high efficiency of DDT as a contact poison against several arthropods

  11. Ronald Ross • Scottish physician, mathematician, poet, playwright, writer, and painter • Bombay 1895 – recruited volunteers to drink water with dead mosquitoes  caused fever but not parasitemia • Switched tactics to having mosquitoes bite infected patients then dissecting the mosquitoes, but was using Culex and Aedes instead of Anopheles until 1897

  12. This day relenting God Hath placed within my hand A wondrous thing: and God Be praised. At his command Seeking his secret deeds With tears and toiling breath, I find thy cunning seeds O million-murdering death I know this little thing A myriad men will save. O death, where is thy sting? Thy victory, O grave?


  14. Clinical Manifestations • FEVER • HA, myalgia, N/V/D, abdominal pain, cough, diarrhea • Anemia, thrombocytopenia, splenomegaly, jaundice • hepatomegaly uncommon • Cerebral malaria with P. falciparum • AMS, seizures, coma • more common in kids

  15. Diagnosis • In Malawi: mother’s report of fever in her child – 93% sensitive, 21% specific • Missionary algorithm: fever and/or diarrhea  treat for malaria for three days  if no better, treat for typhoid for three days  if no better, think • T>37.6 + nail pallor + splenomegaly – 85% sensitive, 41% specific • Thick/thin smear – remains the standard

  16. Diagnosis • Thick smear: one drop of blood on a slide, spread to area 1cm2 • RBCs hemolyzed, parasites and leukocytes detectable • Used to detect and quantify parasitemia • Thin smear: fixed with methanol  no hemolysis • Used to identify species


  18. Malaria at DUMC • Consider malaria in any febrile patient who has been to a malaria-endemic area in the year prior to presentation • In the 2007 JAMA review, 98% of patients with P. falciparum in the US became symptomatic within 3 months of arrival to the US • 96% of patients with non-falciparum malaria became symptomatic within 12 months

  19. Malaria drugs • Quinoline derivatives – inhibit heme polymerase  accumulate free heme which is toxic to the parasites • chloroquine, quinine, quinidine, amodiaquine, mefloquine, halofantrine, primaquine • Artemisinin derivatives – bind iron in malarial pigment  form free radicals toxic to the parasites • Artemisinin, artemether, artesunate • Not available in the US • Clinical resistance has not been documented

  20. Malaria drugs (cont.) • Antifolates – pyrimethamine, sulfonamides, dapsone, proguanil • Antimicrobials – clindamycin, atovaquone, tetracyclines • synergistic with quinolines • active against blood schizonts

  21. Global Eradication Efforts • WHO in 1955 set a goal to eradicate malaria • The US was heavily invested, behind the support of Eisenhower, George Marshall, and JFK "I propose that the United States join with other nations and organizations which are already spending over $50 million a year on anti- malaria activities. In five years, these activities are expected to eradicate this disease." - Eisenhower, addressing Congress in 1953

  22. Global Eradication Efforts – The First Attempt • Efforts were largely based on DDT and chloroquine, which was successful for a time • But insecticide-resistant mosquitoes evolved, and chloroquine-resistant parasites • And there was that issue with fragile eggshells • Funding decreased after the failure of the campaign in the 1950’s and 1960’s

  23. Global Eradication Efforts – The Resurgence • The Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM) • an independent public-private partnership formed in 2002 • was first proposed by the UN Secretary-General, Kofi Annan • Approx 1/3 of the money is donated by the US

  24. Global Eradication Efforts – The Resurgence • President’s Malaria Initiative (2005) • Pledge to increase funding by the US by at least $1.2 billion over five years • Joins USAID, DHHS, CDC, Dept of State • Goal is to provide prevention and treatment measures to 85% of children under 5 and pregnant women

  25. Global Eradication Efforts – The Resurgence • Roll Back Malaria Partnership • Formed in 1998 by WHO, UNICEF, UNDP, World Bank • Aims for coverage of: • 60% of children and pregnant women with ITNs • 60% of malaria cases receive effective therapy within 24 hours • 60% of pregnant women receive intermittent presumptive therapy • 60% of epidemics be detected within two weeks of onset and responded to within 2 more weeks

  26. Global Eradication Efforts – The Resurgence • World Bank’s “Rolling Back Malaria: The Global Strategy and Booster Program“ • Emphasizes the economic cost of malaria (close to 1% of sub-Saharan Africa’s GDP) and the cost-effectiveness of control (eg $2,762 per life saved for a program in Brazil)

  27. Global Eradication Efforts • WHO in 2005 asked members to set a target of 50% reduction in malaria burden by 2010 and 75% by 2015 • Melinda Gates, October 17, 2007: “… the rising concern of people around the world represents an historic opportunity not just to treat malaria or to control it—but to chart a long-term course to eradicate it.”

  28. Bill and Melinda Gates Foundation • $7.8 billion in grants dispersed from inception to March 2007 (not all for malaria) • Projects have included: • successful ITN coverage in Zambia • funding the RTS/S vaccine trial in Mozambique

  29. Current funding is about $2 billion per year • $1 billion donor money • $600 million from endemic countries and their citizens • $400 million R&D

  30. 2006 Sports Illustrated column established a program to distribute insecticide-treated nets (

  31. “I teach you to lie, cheat, and steal, and as soon as my back is turned you wait in line? Get an MRI and get a better medical history” • “If a human being had actually looked at his blood, anywhere along the way, instead of just running tests through the computer, parasites would have jumped right out at them.“ • “Patients sometimes get better. You have no idea why, but unless you give a reason they won't pay you.”

  32. The Backlash

  33. The Backlash “Chronic disease is already the biggest problem for poor and middle-income countries. To concentrate so much on infections is to add to the health burden of the next generation in what are already the world's poorest, unhealthiest places.” -The Economist, 8/9/07

  34. Strategies For Malaria Control • Vector control • eg. insecticides • Exposure prophylaxis • eg. bednets • Clinical management • better drugs, better access • Vaccines

  35. Malaria vaccine • Basic reproductive number R0 for an infection  • R0 = mean # of new cases a single infected case will cause in a population with no immunity and in the absence of interventions to control the infection • If R0 < 1 then the infection will not persist in a population • R0 > 1 then epidemics can occur • 1 – 1/R0 is the proportion of the population that needs to be vaccinated to provide herd immunity (prevent sustained spread)

  36. Herd Immunity Thresholds for Selected Vaccine-Preventable Diseases *4 doses †Modified from Epid Rev 1993;15: 265-302, Am J Prev Med 2001; 20 (4S): 88-153, MMWR 2000; 49 (SS-9); 27-38

  37. The R0 for malaria in Africa is estimated at 50-100 • Therefore to eliminate endemic malaria would require 99% coverage with a lifelong vaccine (that is 100% effective) at 3 months of age

  38. Malaria Vaccine • The first human malaria vaccine was reported in 1973 – but used the bites of thousands of mosquitoes infected with irradiated plasmodia • Current efforts have two broad strategies • subunit vaccines that mimic naturally acquired immunity • experimental model vaccines, eg live attenuated parasites and transmission-blocking antigens

  39. Malaria Vaccine • SPf66 was the first vaccine to undergo field trials after promising phase I trials, but was not more effective than placebo in larger trials • There are currently at least 25 candidate vaccines in development, of which RTS,S/AS02A is the furthest along

  40. Malaria Vaccine • Double-blind RCT of 214 children in Mozambique who received RTS,S/AS02D or Hep B vaccine at 10 weeks, 14 weeks, and 18 weeks of age • Vaccine is made of 2 falciparum surface proteins (RTS and S fused to HbsAg) • Primary endpoint was safety at 6 months • Secondary endpoint was vaccine efficacy at 3 months – which was 65% (5% of children who got the malaria vaccine vs 8% of the controls)

  41. Summary • Consider malaria in any febrile patient with recent travel to an endemic area • Get a thick and thin smear • Poetry about malaria is actually not very romantic • Although the malaria epidemic continues largely unabated, there is growing political and financial will to push for eradication

  42. “ I hope you will judge yourselves not on your professional accomplishments alone, but also on how well you have addressed the world’s deepest inequities… on how well you treated people a world away who have nothing in common with you but their humanity.” - Bill Gates June 7, 2007

  43. References • Joy DA, Feng X, et al. Early Origin and recent expansion of Plasmodium falciparum. Science; 2003 Apr 11;300(5617):318-21. • Singh B, Kim Sung L, et al. A large focus of naturally acquired Plasmodium knowlesi infections in human beings. Lancet 2004 Mar 27;363(9414):1017-24. • Anderson RM, May RM. "Population biology of infectious diseases: Part I". Nature280 (5721): 361-7. • CDC: • Redd SC; Kazembe PN; et al. Clinical algorithm for treatment of Plasmodium falciparum malaria in children. AU Lancet 1996 Jan 27;347(8996):223-7. • Hanson JP, Dondorp AM, Day NP. Malaria treatment in the United States. JAMA. 2007 May 23;297(20):2264-77. • Resolution WHA. 58.2. Malaria control. In: Fifty-eighth World Health Assembly, Resolutions and Decisions Annex. Geneva: WHO; 2005. Available at: • Global Partnership to Roll Back Malaria. The African Summit on Roll Back Malaria, Abuja, Nigeria, 25 April 2000. Geneva: WHO; 2000 (WHO/CDS/RBM/2000.17). Available at:

  44. Matuschewski K, Mueller AK (2007). Vaccines against malaria - an update FEBS Journal 274 (18), 4680–4687. • Aponte JJ, Aide P, et al. Safety of the RTS,S/AS02D candidate malaria vaccine in infants living in a highly endemic area of Mozambique: a double blind randomised controlled phase I/IIb trial In Press, Corrected Proof, Available online 18 October 2007et al. • VS Moorthy, MF Good and AVS Hill, Malaria vaccine developments, Lancet363 (2004), pp. 150–156. • Russell PF. Man’s Mastery of Malaria. London: Oxford University Press 1955. • Clyde DF, Most H, McCarthy VC, Vanderberg JP. Immunization of man against sporozoite-induced falciparum malaria. Am J Med Sci 1973; 266: 169-77. • SI Hay, CA Guerra, AJ Tatem, AM Noor and RW Snow, The global distribution and population at risk of malaria: past, present and future, Lancet Infect Dis4 (2004), pp. 327–336. • Cohen S, McGregor GI & Carrington S (1961) Gamma-globulin and acquired immunity to human malaria. Nature 192, 733–737. • Sherman, IW. The Power of Plagues. ASM Press, Washington DC, 2006.