Bad AirBad Air

Thomas HollandThomas Holland

October 25, 2007October 25, 2007

““What is the most repeated failure What is the most repeated failure in all of global health? It could in all of global health? It could well be the commitment to well be the commitment to eradicate malaria.”eradicate malaria.”

Bill Gates, October 17,2007Bill Gates, October 17,2007

45 minutes from now 45 minutes from now you will know all of you will know all of this:this: Malaria epidemiologyMalaria epidemiology A historical perspective on malariaA historical perspective on malaria Some romantic malaria-themed poetry Some romantic malaria-themed poetry

to use on your next dateto use on your next date Clinical manifestations and diagnosisClinical manifestations and diagnosis Basics of treatmentBasics of treatment Malaria at DUMCMalaria at DUMC Global eradication effortsGlobal eradication efforts Why the VA Jets will win the Turkey Why the VA Jets will win the Turkey

Bowl this yearBowl this year

What is malaria?What is malaria?

Malaria is a vector-borne disease Malaria is a vector-borne disease caused by protozoa:caused by protozoa:– P. falciparumP. falciparum– P. vivaxP. vivax– P. ovaleP. ovale– P. malariaeP. malariae– P. knowlesiP. knowlesi

Worldwide DistributionWorldwide 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 distributionWorldwide distribution

http://en.wikipedia.org/wiki/Malaria

Malaria EpidemiologyMalaria Epidemiology

300-500 million cases per year 300-500 million cases per year worldwideworldwide

700,000 to 2.7 million deaths per 700,000 to 2.7 million deaths per yearyear

~1300 cases in the US reported to ~1300 cases in the US reported to the CDC in 2004 the CDC in 2004

Average 2 cases per year at DUMCAverage 2 cases per year at DUMC

Malaria in AntiquityMalaria in Antiquity

Genetic analysis has suggested that a Genetic analysis has suggested that a virulent Plasmodia falciparum evolved 6000 virulent Plasmodia falciparum evolved 6000 years ago (“Malaria’s Eve”) around the time years ago (“Malaria’s Eve”) around the time of the emergence of agricultural societies of the emergence of agricultural societies

However it appears that some populations However it appears that some populations are 50,000 to 400,000 years old are 50,000 to 400,000 years old ie, older ie, older than homo sapiensthan homo sapiens

Malaria in antiquityMalaria in antiquity

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

www.wikipedia.org

Nobel Prizes for work Nobel Prizes for work on malariaon malaria 1902 – Ronald Ross1902 – Ronald Ross

1907 – Charles Louis Alphonse Laveran 1907 – Charles Louis Alphonse Laveran – discovered that malaria is caused by a protozoandiscovered that malaria is caused by a protozoan

1927 – Julius Wagner-Juaregg1927 – Julius Wagner-Juaregg– for his discovery of the therapeutic value of malaria for his discovery of the therapeutic value of malaria

inoculation in the treatment of dementia paralytica inoculation in the treatment of dementia paralytica (caused by neurosyphilis)(caused by neurosyphilis)

1948 - Paul Hermann Müller1948 - Paul Hermann Müller– For his discovery of the high efficiency of DDT as a For his discovery of the high efficiency of DDT as a

contact poison against several arthropods contact poison against several arthropods

Ronald RossRonald Ross

Scottish physician, Scottish physician, mathematician, poet, mathematician, poet, playwright, writer, and painterplaywright, writer, and painter

Bombay 1895 – recruited Bombay 1895 – recruited volunteers to drink water with volunteers to drink water with dead mosquitoes dead mosquitoes caused caused fever but not parasitemiafever but not parasitemia

Switched tactics to having Switched tactics to having mosquitoes bite infected mosquitoes bite infected patients then dissecting the patients then dissecting the mosquitoes, but was using mosquitoes, but was using CulexCulex and and AedesAedes instead of instead of Anopheles Anopheles until 1897 until 1897

http://en.wikipedia.org/wiki/Ronald_ross

This day relenting GodHath placed within my handA wondrous thing: and God

Be praised. At his command

Seeking his secret deedsWith tears and toiling breath,

I find thy cunning seedsO million-murdering death

I know this little thingA myriad men will save.

O death, where is thy sting?Thy victory, O grave?

http://www.utdol.com

Clinical ManifestationsClinical Manifestations

FEVERFEVER HA, myalgia, N/V/D, abdominal pain, HA, myalgia, N/V/D, abdominal pain,

cough, diarrheacough, diarrhea Anemia, thrombocytopenia, Anemia, thrombocytopenia,

splenomegaly, jaundicesplenomegaly, jaundice– hepatomegaly uncommonhepatomegaly uncommon

Cerebral malaria with P. falciparumCerebral malaria with P. falciparum– AMS, seizures, comaAMS, seizures, coma– more common in kidsmore common in kids

DiagnosisDiagnosis

In Malawi: mother’s report of fever in her In Malawi: mother’s report of fever in her child – 93% sensitive, 21% specificchild – 93% sensitive, 21% specific

Missionary algorithm: fever and/or diarrhea Missionary algorithm: fever and/or diarrhea treat for malaria for three days treat for malaria for three days if no if no better, treat for typhoid for three days better, treat for typhoid for three days if if no better, thinkno better, think

T>37.6 + nail pallor + splenomegaly – 85% T>37.6 + nail pallor + splenomegaly – 85% sensitive, 41% specificsensitive, 41% specific

Thick/thin smear – remains the standardThick/thin smear – remains the standard

DiagnosisDiagnosis

Thick smear: one drop of blood on a Thick smear: one drop of blood on a slide, spread to area 1cmslide, spread to area 1cm22

– RBCs hemolyzed, parasites and RBCs hemolyzed, parasites and leukocytes detectableleukocytes detectable

– Used to detect and quantify parasitemiaUsed to detect and quantify parasitemia

Thin smear: fixed with methanol Thin smear: fixed with methanol no hemolysisno hemolysis– Used to identify speciesUsed to identify species

www.cdc.gov www.utdol.com

Malaria at DUMCMalaria at DUMC

Consider malaria in any febrile patient Consider malaria in any febrile patient who has been to a malaria-endemic who has been to a malaria-endemic area in the year prior to presentationarea in the year prior to presentation– In the 2007 JAMA review, 98% of patients In the 2007 JAMA review, 98% of patients

with with P. falciparumP. falciparum in the US became in the US became symptomatic within 3 months of arrival to symptomatic within 3 months of arrival to the USthe US

– 96% of patients with non-96% of patients with non-falciparumfalciparum malaria became symptomatic within 12 malaria became symptomatic within 12 monthsmonths

Malaria drugsMalaria drugs

Quinoline derivatives – inhibit heme Quinoline derivatives – inhibit heme polymerase polymerase accumulate free heme which accumulate free heme which is toxic to the parasitesis toxic to the parasites– chloroquine, quinine, quinidine, amodiaquine, chloroquine, quinine, quinidine, amodiaquine,

mefloquine, halofantrine, primaquinemefloquine, halofantrine, primaquine

Artemisinin derivatives – bind iron in malarial Artemisinin derivatives – bind iron in malarial pigment pigment form free radicals toxic to the form free radicals toxic to the parasitesparasites– Artemisinin, artemether, artesunateArtemisinin, artemether, artesunate– Not available in the USNot available in the US– Clinical resistance has not been documentedClinical resistance has not been documented

Malaria drugs (cont.)Malaria drugs (cont.)

Antifolates – pyrimethamine, sulfonamides, Antifolates – pyrimethamine, sulfonamides, dapsone, proguanildapsone, proguanil

Antimicrobials – clindamycin, atovaquone, Antimicrobials – clindamycin, atovaquone, tetracyclinestetracyclines– synergistic with quinolines synergistic with quinolines – active against blood schizontsactive against blood schizonts

Global Eradication Global Eradication EffortsEfforts

WHO in 1955 set a goal to eradicate malariaWHO in 1955 set a goal to eradicate malaria The US was heavily invested, behind the The US was heavily invested, behind the

support of Eisenhower, George Marshall, and support of Eisenhower, George Marshall, and JFKJFK

"I propose that the United States join with "I propose that the United States join with other other nations and organizations which are nations and organizations which are already already spending over $50 million a year spending over $50 million a year on anti-on anti- malaria activities. In five years, malaria activities. In five years, these these activities are expected to activities are expected to eradicate this eradicate this disease." disease."

- Eisenhower, addressing Congress in 1953- Eisenhower, addressing Congress in 1953

Global Eradication Global Eradication Efforts – The First Efforts – The First AttemptAttempt Efforts were largely based on DDT and Efforts were largely based on DDT and

chloroquine, which was successful for a chloroquine, which was successful for a timetime– But insecticide-resistant mosquitoes But insecticide-resistant mosquitoes

evolved, and chloroquine-resistant parasitesevolved, and chloroquine-resistant parasites– And there was that issue with fragile And there was that issue with fragile

eggshellseggshells

Funding decreased after the failure of Funding decreased after the failure of the campaign in the 1950’s and 1960’sthe campaign in the 1950’s and 1960’s

Global Eradication Global Eradication Efforts – The Efforts – The ResurgenceResurgence The Global Fund to Fight AIDS, The Global Fund to Fight AIDS,

Tuberculosis and Malaria (GFATM) Tuberculosis and Malaria (GFATM) – an independent public-private an independent public-private

partnership formed in 2002partnership formed in 2002– was first proposed by the UN was first proposed by the UN

Secretary-General, Kofi Annan Secretary-General, Kofi Annan – Approx 1/3 of the money is donated Approx 1/3 of the money is donated

by the USby the US

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

– Pledge to increase funding by the US by Pledge to increase funding by the US by at least $1.2 billion over five yearsat least $1.2 billion over five years

– Joins USAID, DHHS, CDC, Dept of StateJoins USAID, DHHS, CDC, Dept of State– Goal is to provide prevention and Goal is to provide prevention and

treatment measures to 85% of children treatment measures to 85% of children under 5 and pregnant women under 5 and pregnant women

Global Eradication Global Eradication Efforts – The Efforts – The ResurgenceResurgence Roll Back Malaria PartnershipRoll Back Malaria Partnership

– Formed in 1998 by WHO, UNICEF, UNDP, Formed in 1998 by WHO, UNICEF, UNDP, World Bank World Bank

– Aims for coverage of:Aims for coverage of: 60% of children and pregnant women with ITNs60% of children and pregnant women with ITNs 60% of malaria cases receive effective therapy 60% of malaria cases receive effective therapy

within 24 hourswithin 24 hours 60% of pregnant women receive intermittent 60% of pregnant women receive intermittent

presumptive therapypresumptive therapy 60% of epidemics be detected within two weeks 60% of epidemics be detected within two weeks

of onset and responded to within 2 more weeksof onset and responded to within 2 more weeks

Global Eradication Global Eradication Efforts – The Efforts – The ResurgenceResurgence World Bank’s “World Bank’s “Rolling Back Rolling Back

Malaria: The Global Strategy and Malaria: The Global Strategy and Booster Program“Booster Program“– Emphasizes the economic cost of Emphasizes the economic cost of

malaria (close to 1% of sub-Saharan malaria (close to 1% of sub-Saharan Africa’s GDP) and the cost-Africa’s GDP) and the cost-effectiveness of control (eg $2,762 effectiveness of control (eg $2,762 per life saved for a program in per life saved for a program in Brazil)Brazil) http://siteresources.worldbank.org/INTMALARIA/Resources/

377501-1114188195065/execsum.pdf

Global Eradication Global Eradication EffortsEfforts WHO in 2005 asked members to set a WHO in 2005 asked members to set a

target of 50% reduction in malaria target of 50% reduction in malaria burden by 2010 and 75% by 2015burden by 2010 and 75% by 2015

Melinda Gates, October 17, 2007:Melinda Gates, October 17, 2007:“… “… the rising concern of people around the the rising concern of people around the

world represents an historic opportunity not world represents an historic opportunity not just to treat malaria or to control it—but to just to treat malaria or to control it—but to chart a long-term course to eradicate it.”chart a long-term course to eradicate it.”

Bill and Melinda Gates FoundationBill and Melinda Gates Foundation– $7.8 billion in grants dispersed from $7.8 billion in grants dispersed from

inception to March 2007 (not all for inception to March 2007 (not all for malaria)malaria)

– Projects have included:Projects have included: successful ITN coverage in Zambiasuccessful ITN coverage in Zambia funding the RTS/S vaccine trial in funding the RTS/S vaccine trial in

MozambiqueMozambique

Current funding is about $2 billion Current funding is about $2 billion per yearper year– $1 billion donor money$1 billion donor money– $600 million from endemic countries $600 million from endemic countries

and their citizensand their citizens– $400 million R&D$400 million R&D

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

““I teach you to lie, cheat, I teach you to lie, cheat, and steal, and as soon as my and steal, and as soon as my back is turned you wait in back is turned you wait in line? Get an MRI and get a line? Get an MRI and get a better medical history”better medical history”

““If a human being had If a human being had actually looked at his blood, actually looked at his blood, anywhere along the way, anywhere along the way, instead of just running tests instead of just running tests through the computer, through the computer, parasites would have parasites would have jumped right out at them.“jumped right out at them.“

““Patients sometimes get Patients sometimes get

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

http://economist.com/world/international/displaystory.cfm?story_id=9616897

The BacklashThe Backlash

The BacklashThe 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 Strategies For Malaria ControlControl

Vector controlVector control– eg. insecticideseg. insecticides

Exposure prophylaxisExposure prophylaxis– eg. bednetseg. bednets

Clinical managementClinical management– better drugs, better accessbetter drugs, better access

VaccinesVaccines

Malaria vaccineMalaria vaccine

Basic reproductive number RBasic reproductive number R00 for an infection for an infection – RR00 = mean # of new cases a single infected case will = mean # of new cases a single infected case will

cause in a population with no immunity and in the cause in a population with no immunity and in the absence of interventions to control the infectionabsence of interventions to control the infection

If RIf R00 < 1 then the infection will not persist in a < 1 then the infection will not persist in a populationpopulation

RR00 > 1 then epidemics can occur > 1 then epidemics can occur

1 – 1/R1 – 1/R00 is the proportion of the population that is the proportion of the population that needs to be vaccinated to provide herd needs to be vaccinated to provide herd immunity (prevent sustained spread)immunity (prevent sustained spread)

Herd Immunity Thresholds for Selected Herd Immunity Thresholds for Selected Vaccine-Preventable DiseasesVaccine-Preventable Diseases

Immunization LevelsImmunization LevelsDiseaseDisease RRoo Herd Herd

ImmunityImmunity1999199919-35 19-35

MonthsMonths

1997-1997-19981998Pre-Pre-

SchoolSchool

DiphtheriDiphtheriaa

6-76-7 85%*85%* 83%*83%* 9%9%

MeaslesMeasles 12-1812-18 83-94%83-94% 92%92% 96%96%

MumpsMumps 4-74-7 75-86%75-86% 92%92% 97%97%

PertussisPertussis 12-1712-17 92-94%92-94% 83%*83%* 97%97%

PolioPolio 5-75-7 80-86%80-86% 90%90% 97%97%

RubellaRubella 6-76-7 83-85%83-85% 92%92% 97%97%

SmallpoxSmallpox 5-75-7 80-85%80-85% ____ ____*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

The RThe R00 for malaria in Africa is for malaria in Africa is estimated at 50-100estimated at 50-100

Therefore to eliminate endemic Therefore to eliminate endemic malaria would require 99% malaria would require 99% coverage with a lifelong vaccine coverage with a lifelong vaccine (that is 100% effective) at 3 (that is 100% effective) at 3 months of agemonths of age

Malaria VaccineMalaria Vaccine

The first human malaria vaccine was The first human malaria vaccine was reported in 1973 – but used the bites of reported in 1973 – but used the bites of thousands of mosquitoes infected with thousands of mosquitoes infected with irradiated plasmodiairradiated plasmodia

Current efforts have two broad strategiesCurrent efforts have two broad strategies– subunit vaccines that mimic naturally subunit vaccines that mimic naturally

acquired immunityacquired immunity– experimental model vaccines, eg live experimental model vaccines, eg live

attenuated parasites and transmission-attenuated parasites and transmission-blocking antigens blocking antigens

Malaria VaccineMalaria Vaccine

SPf66 was the first vaccine to undergo SPf66 was the first vaccine to undergo field trials after promising phase I field trials after promising phase I trials, but was not more effective than trials, but was not more effective than placebo in larger trialsplacebo in larger trials

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

Malaria VaccineMalaria Vaccine

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

SummarySummary

Consider malaria in any febrile patient Consider malaria in any febrile patient with recent travel to an endemic areawith recent travel to an endemic area

Get a thick and thin smearGet a thick and thin smear Poetry about malaria is actually not Poetry about malaria is actually not

very romanticvery romantic Although the malaria epidemic Although the malaria epidemic

continues largely unabated, there is continues largely unabated, there is growing political and financial will to growing political and financial will to push for eradication push for eradication

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

June 7, 2007

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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". Nature 280 (5721): 361-7.

CDC: http://www.bt.cdc.gov/agent/smallpox/training/overview/CDC: http://www.bt.cdc.gov/agent/smallpox/training/overview/

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.

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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: http://whqlibdoc.who.int/hq/2000/WHO_CDS_RBM_2000.17.pdf

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, Lancet 363 (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 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.