Bad Air Thomas Holland October 25, 2007

“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

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

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

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 Dis 4 (2004), pp. 327–336.

Worldwide distribution

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

Malaria in Antiquity 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 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 However it appears that some populations are 50,000 to 400,000 years old  ie, older than homo sapiens 

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

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

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

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?

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

Diagnosis In Malawi: mother’s report of fever in her child – 93% sensitive, 21% specific 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 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> nail pallor + splenomegaly – 85% sensitive, 41% specific T> nail pallor + splenomegaly – 85% sensitive, 41% specific Thick/thin smear – remains the standard Thick/thin smear – remains the standard

Diagnosis Thick smear: one drop of blood on a slide, spread to area 1cm 2 Thick smear: one drop of blood on a slide, spread to area 1cm 2 –RBCs hemolyzed, parasites and leukocytes detectable –Used to detect and quantify parasitemia Thin smear: fixed with methanol  no hemolysis Thin smear: fixed with methanol  no hemolysis –Used to identify species

Malaria at DUMC Consider malaria in any febrile patient who has been to a malaria-endemic area in the year prior to presentation 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

Malaria drugs Quinoline derivatives – inhibit heme polymerase  accumulate free heme which is toxic to the parasites 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 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

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

Global Eradication Efforts WHO in 1955 set a goal to eradicate malaria WHO in 1955 set a goal to eradicate malaria The US was heavily invested, behind the support of Eisenhower, George Marshall, and JFK 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 Eisenhower, addressing Congress in 1953

Global Eradication Efforts – The First Attempt Efforts were largely based on DDT and chloroquine, which was successful for a time 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 Funding decreased after the failure of the campaign in the 1950’s and 1960’s

Global Eradication Efforts – The Resurgence The Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM) 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

Global Eradication Efforts – The Resurgence President’s Malaria Initiative (2005) 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

Global Eradication Efforts – The Resurgence Roll Back Malaria Partnership 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 children and pregnant women with ITNs 60% of malaria cases receive effective therapy within 24 hours 60% of malaria cases receive effective therapy within 24 hours 60% of pregnant women receive intermittent presumptive therapy 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 60% of epidemics be detected within two weeks of onset and responded to within 2 more weeks

Global Eradication Efforts – The Resurgence World Bank’s “Rolling Back Malaria: The Global Strategy and Booster Program“ 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) /execsum.pdf

Global Eradication Efforts WHO in 2005 asked members to set a target of 50% reduction in malaria burden by 2010 and 75% by 2015 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: 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.”

Bill and Melinda Gates Foundation 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 successful ITN coverage in Zambia funding the RTS/S vaccine trial in Mozambique funding the RTS/S vaccine trial in Mozambique

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

2006 Sports Illustrated column established a program to distribute insecticide-treated nets (nothingbutnets.com) 2006 Sports Illustrated column established a program to distribute insecticide-treated nets (nothingbutnets.com)

“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” “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.“ “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.” “Patients sometimes get better. You have no idea why, but unless you give a reason they won't pay you.”

tional/displaystory.cfm?story_id= 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 -The Economist, 8/9/07

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

Malaria vaccine Basic reproductive number R 0 for an infection  Basic reproductive number R 0 for an infection  –R 0 = 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 R 0 < 1 then the infection will not persist in a population If R 0 < 1 then the infection will not persist in a population R 0 > 1 then epidemics can occur R 0 > 1 then epidemics can occur 1 – 1/R 0 is the proportion of the population that needs to be vaccinated to provide herd immunity (prevent sustained spread) 1 – 1/R 0 is the proportion of the population that needs to be vaccinated to provide herd immunity (prevent sustained spread)

Herd Immunity Thresholds for Selected Vaccine-Preventable Diseases Immunization Levels Disease RoRoRoRo Herd Immunity Months Pre-School Diphtheria6-785%*83%*9% Measles %92%96% Mumps %92%97% Pertussis %83%*97% Polio %90%97% Rubella %92%97% Smallpox %____ *4 doses † Modified from Epid Rev 1993;15: , Am J Prev Med 2001; 20 (4S): , MMWR 2000; 49 (SS-9); 27-38

The R 0 for malaria in Africa is estimated at The R 0 for malaria in Africa is estimated at Therefore to eliminate endemic malaria would require 99% coverage with a lifelong vaccine (that is 100% effective) at 3 months of age Therefore to eliminate endemic malaria would require 99% coverage with a lifelong vaccine (that is 100% effective) at 3 months of age

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

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 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 There are currently at least 25 candidate vaccines in development, of which RTS,S/AS02A is the furthest along

Malaria Vaccine Double-blind RCT of 214 children in Mozambique who received 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)

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

“ 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

References Joy DA, Feng X, et al. Early Origin and recent expansion of Plasmodium falciparum. Science; 2003 Apr 11;300(5617): 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): Anderson RM, May RM. "Population biology of infectious diseases: Part I". Nature 280 (5721): CDC: CDC: Redd SC; Kazembe PN; et al. Clinical algorithm for treatment of Plasmodium falciparum malaria in children. AU Lancet 1996 Jan 27;347(8996): Hanson JP, Dondorp AM, Day NP. Malaria treatment in the United States. JAMA May 23;297(20): Resolution WHA Malaria control. In: Fifty-eighth World Health Assembly, Resolutions and Decisions Annex. Geneva: WHO; Available at: Global Partnership to Roll Back Malaria. The African Summit on Roll Back Malaria, Abuja, Nigeria, 25 April Geneva: WHO; 2000 (WHO/CDS/RBM/ ). Available at:

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 2007 et al. VS Moorthy, MF Good and AVS Hill, Malaria vaccine developments, Lancet 363 (2004), pp. 150–156. Russell PF. Man’s Mastery of Malaria. London: Oxford University Press Clyde DF, Most H, McCarthy VC, Vanderberg JP. Immunization of man against sporozoite-induced falciparum malaria. Am J Med Sci 1973; 266: 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 Dis 4 (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.