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:
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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
What is malaria?
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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
http://en.wikipedia.org/wiki/Malaria
Malaria Epidemiology
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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
Malaria in Antiquity
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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
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Malaria in antiquity
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Enlarged spleen,
periodic fevers,
headaches, and
chills are described
in the Ebers
papyrus (~1550
BC) as well as in
ancient Chinese
medical texts
www.wikipedia.org
Nobel Prizes for work on
malaria
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1902 – Ronald Ross
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1907 – Charles Louis Alphonse Laveran
– discovered that malaria is caused by a protozoan
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1927 – Julius Wagner-Juaregg
– for his discovery of the therapeutic value of malaria
inoculation in the treatment of dementia paralytica
(caused by neurosyphilis)
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1948 - Paul Hermann Müller
– For his discovery of the high efficiency of DDT as a contact
poison against several arthropods
Ronald Ross
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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
http://en.wikipedia.org/wiki/Ronald_ross
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?
http://www.utdol.com
Clinical Manifestations
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FEVER
HA, myalgia, N/V/D, abdominal pain, cough,
diarrhea
Anemia, thrombocytopenia, splenomegaly,
jaundice
– hepatomegaly uncommon
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Cerebral malaria with P. falciparum
– AMS, seizures, coma
– more common in kids
Diagnosis
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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
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T>37.6 + nail pallor + splenomegaly – 85%
sensitive, 41% specific
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Thick/thin smear – remains the standard
Diagnosis
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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
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Thin smear: fixed with methanol  no
hemolysis
– Used to identify species
www.cdc.gov
www.utdol.com
Malaria at DUMC
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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
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Quinoline derivatives – inhibit heme polymerase 
accumulate free heme which is toxic to the
parasites
– chloroquine, quinine, quinidine, amodiaquine, mefloquine,
halofantrine, primaquine
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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.)
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Antifolates – pyrimethamine, sulfonamides,
dapsone, proguanil
Antimicrobials – clindamycin, atovaquone,
tetracyclines
– synergistic with quinolines
– active against blood schizonts
Global Eradication Efforts
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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 antimalaria activities. In five years, these
activities are expected to eradicate this
disease."
- Eisenhower, addressing Congress in 1953
Global Eradication Efforts
– The First Attempt
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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
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Funding decreased after the failure of the
campaign in the 1950’s and 1960’s
Global Eradication Efforts
– The Resurgence
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The Global Fund to Fight AIDS,
Tuberculosis and Malaria (GFATM)
– an independent public-private partnership
formed in 2002
– was first proposed by the UN SecretaryGeneral, Kofi Annan
– Approx 1/3 of the money is donated by
the US
Global Eradication Efforts
– The Resurgence
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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
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Roll Back Malaria Partnership
– Formed in 1998 by WHO, UNICEF, UNDP, World
Bank
– Aims for coverage of:
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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
Global Eradication Efforts
– The Resurgence
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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)
http://siteresources.worldbank.org/INTMALARIA/Resources/3775011114188195065/execsum.pdf
Global Eradication Efforts
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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 longterm course to eradicate it.”
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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
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Current funding is about $2 billion per
year
– $1 billion donor money
– $600 million from endemic countries and
their citizens
– $400 million R&D
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2006 Sports Illustrated column established a
program to distribute insecticide-treated
nets (nothingbutnets.com)
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“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.”
The Backlash
http://economist.com/world/interna
tional/displaystory.cfm?story_id=96
16897
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
Strategies For Malaria Control
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Vector control
– eg. insecticides
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Exposure prophylaxis
– eg. bednets
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Clinical management
– better drugs, better access
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Vaccines
Malaria vaccine
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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
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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)
Herd Immunity Thresholds for Selected
Vaccine-Preventable Diseases
Immunization Levels
1999
1997-1998
19-35
Pre-School
Months
Disease
Ro
Herd
Immunity
Diphtheria
6-7
85%*
83%*
9%
Measles
12-18
83-94%
92%
96%
Mumps
4-7
75-86%
92%
97%
12-17
92-94%
83%*
97%
Polio
5-7
80-86%
90%
97%
Rubella
6-7
83-85%
92%
97%
Smallpox
5-7
80-85%
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__
Pertussis
*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
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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
Malaria Vaccine
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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
Malaria Vaccine
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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
Malaria Vaccine
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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
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Vaccine is made of 2 falciparum surface proteins
(RTS and S fused to HbsAg)
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Primary endpoint was safety at 6 months
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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
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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
“ 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
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Joy DA, Feng X, et al. Early Origin and recent expansion of Plasmodium falciparum. Science; 2003 Apr
11;300(5617):318-21.
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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.
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Anderson RM, May RM. "Population biology of infectious diseases: Part I". Nature 280 (5721): 361-7.
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CDC: http://www.bt.cdc.gov/agent/smallpox/training/overview/
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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.
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Hanson JP, Dondorp AM, Day NP. Malaria treatment in the United States.
JAMA. 2007 May 23;297(20):2264-77.
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Resolution WHA. 58.2. Malaria control. In: Fifty-eighth World Health Assembly, Resolutions and
Decisions Annex. Geneva: WHO; 2005. Available at:
http://www.who.int/gb/ebwha/pdf_files/WHA58/WHA58_2-en.pdf
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
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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.
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VS Moorthy, MF Good and AVS Hill, Malaria vaccine developments, Lancet 363 (2004), pp. 150–156.
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Russell PF. Man’s Mastery of Malaria. London: Oxford University Press 1955.
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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.
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Sherman, IW. The Power of Plagues. ASM Press, Washington DC, 2006.