Malaria is transmitted to humans through the bites of infected female Anopheles mosquitoes. The parasite has a complex life cycle involving the liver and red blood cells. Clinical manifestations include fever and flu-like symptoms. Diagnosis is usually by blood smear microscopy. Treatment involves antimalarial drug combinations to prevent resistance. Prevention focuses on insecticide-treated bed nets, repellents, and reducing mosquito habitats. Accurate diagnosis is challenging in resource-poor areas where malaria symptoms overlap with other fevers like pneumonia. This can lead to overdiagnosis of malaria and underdiagnosis of other conditions.

1. Malaria
Charis Segeritz and Jo-Ann Osei-Twum
January 21, 2008

2. Overview
1.) Malaria: Pathology
• Transmission
– How and through what route?
– Main reservoirs?
– Prevention?
• Life cycle
– Tissue schizogony
– Erythrocytic schizogony
– Sporogony
• Clinical manifestation
• High risk groups
• Diagnosis
• Treatment
• Use of genetically modified
mosquitoes
2.) Malaria: Discussion
• Malaria misdiagnosis
• Malaria eradication

3. Transmission
• How and through which route does Malaria infect
humans?
– transmitted by the bite of an infected female
Anopheles mosquito most frequently between dusk
and dawn
– risk of transmission is increased through exposure
 between dusk and dawn
• in rural areas
• at the end of the rainy season
• below 2000m
– rarely:
• transmission by blood transfusion
• Transmission by shared needle use
• Congenital transmission from mother to fetus

4. Transmission
• What are the main reservoirs for the disease?
– infection caused by eukaryotic single-celled microorganism of genus
Plasmodium
• four species infecting humans:
 Plasmodium falciparum (may be fatal, sub-Saharan Africa,
principal cause of malaria deaths in young children in Africa)
 Plasmodium vivax (most widespread, but rarely fatal, Indian
subcontinent)
 Plasmodium ovale (least common, West Africa)
 Plasmodium malariae (worldwide, but low frequency)
• differences
 Morphology
 Immunology
 Geographical distribution
 Relapse pattern
 Drug response

5. Transmission
• What can be done in order to prevent transmission?
– avoid mosquitoes and bites
• physical barriers: mosquito nets, clothing
• chemical barriers:
– repellents: keep mosquitoes from biting
» DEET
» “natural based” repellents
» other synthetic repellents
– insecticides: kill mosquitoes
» treated mosquito nets
» treated clothing
» DDT
– chemoprophylactic drugs

6. Life cycle
• Extremely complex
• Involves various proteins that ensure intracellular and extra-cellular
survival
• Invasion of different cell types
• Evasion of the host immune system
• Three stages
– Tissue Schizogony
– Erythrocyte Schizogony
– Sporogony

7. Tissue Schizogony [A]
• Mosquitoes inject the parasite (sporozoites) into the host
bloodstream [1]
• Sporozoites travel to the liver and penetrate liver cells (hepatocytes)
• Invasion [2]
– mediated by thrombospondin domains of the circumsporozoite
protein and the thrombospondin-related adhesive protein on
sporozoites
– bind to heparin sulphate proteoglycans on hepatocytes
• Asexual replication [3]
– 9-16 days

8. Tissue Schizogony [A]
One sporozoite [2]
Tens of thousands of merozoites [3]
Merozoites released into blood stream [4]
One merozoite invades one red blood cell [5]

9. http://www.cdc.gov/malaria/biology/life_cycle.htm

10. Erythrocytic Schizogony [B]
• Merozoites invade erythrocytes [5]
– Apical reorientation
– Junction formation
– Signalling
• Recognition
– Merozoite surface proteins interact with sialic acid residues
• Invasion
– Erythrocyte binding antigen 175 interacts with glycophorin A
on erythrocytes
• P. falciparum erythrocytes membrane protein 1 (PfEMP1)
– Parasite protein
– Expressed at the surface of infected RBC
– Bind to various host cell receptors
• Endothelium
• Placenta

11. Erythrocytic Schizogony [B]
• In the RBC, merozoites undergo asexual division
– series of developmental stages
• Early trophozoite
– “ring form”
• Trophozoite
– Highly metabolic
» Glycolysis
» Ingestion of host cytoplasm
» Proteolysis of hemoglobin
– Rounds of nuclear division without cytokinesis forming
schizonts
» schizonts contain 20 merozoites, these are released
once the RBC is lyzed [6]
– Cycle of invasion-multiplication-release is repeated
– Some merozoites differentiate into male and female
gametocytes [7]

12. Sporogony [C]
• Gametocytes are ingested into the midgut of feeding mosquitoes [8]
• Fertilization
– Gametes fuse [9]
– Zygote formation
– Development of an oocyst [11]
• Sporogony in oocyst produces many sporozoites
– oocyst raptures releasing sporozoites [12]
– sporozoites migrate to salivary glands
• cycle begins once a mosquito bites a host [1]

13. Clinical manifestations in humans
• develop 6 days - several months after infected mosquito bite
• characterized by fever and “flu-like” symptoms:
– myalgias
– headache
– abdominal pain
– malaise
• often rigors and chills
• classically described alternate-day fevers or other periodic fevers are often not
present
• severe malaria (due to P.falciparum) may cause . . .
– seizures
– coma
– renal and respiratory failure
– anemia (= blood loss), even cerebral anemia (= infected erythrocytes obstruct small blood
vessels in brain, often fatal, especially in infants)
– may lead to death
• dormancy
– P. ovale and P. vivax: hyponozoites
• Dormant liver stages
• Remain in organ for weeks/years before onset of new round of pre-erythrocytic schizogony 
relapses of malaria infection
– P. malariae
• May have long-lasting blood-stage infections that persist in human asymptomatically for several
decades if left untreated

14. High risk groups
• overall case-fatality rate of P. falciparum malaria imported into
Canada varies from approximately 1% to 5% and increases to 30%
for those > 70 years of age
• children
• pregnant women
Diagnosis
• Combination of clinical observations, case history and diagnostic
tests (microscopic examination of blood or rapid “dipstick” tests)
• the symptoms of malaria are non-specific and diagnosis is not
possible without a blood film
• the most important factors that determine patient survival are
early diagnosis and appropriate therapy
• the majority of infections and deaths due to malaria are
preventable

15. Treatment
• Problems:
– widespread resistance of P. falciparum to chloroquine 
complicates prevention and treatment of malaria: drug-resistant
strains of malaria are now common in much of the world
– Insecticide-resistant strains of mosquito
– Lack of licensed malaria vaccines of proven efficacy

16. Treatment
• Solution:
– Combination therapy, e.g. Artemisinin +Fansidar/Mefloquine
– Quinine
• First widely used antimalarial treatment
• From bark of Andean Cinchona tree
– Fansidar and Chloroquine
• Most commonly used
• Most affordable antimalarial drugs
• Goals:
– Reduce antimalarial resistance
– Prolong useful life of current drugs
– Three combined strategies to reduce malaria transmission:
• Develop clinically approved malaria vaccines
• Drug treatment
• Vector control

17. Genetically Modified Mosquitoes
Prevent the transmission of the parasite
Germ-line transformations Identification of effector molecules
Transgenic mosquitoes

18. Genetically Modified Mosquitoes
• Well studied in the laboratory
• Must survive in the wild
• Out-compete their wild-type counterparts
• Genetic modifications must be permanent

19. Discussion: Malaria misdiagnosis
“In a recent study of children reporting to health centres in Uganda,
Karin Kallander and colleagues found that 30% had symptoms
compatible with both pneumonia and malaria and required dual
treatment. This report, and previous studies, have concluded that
community treatment of all childhood fevers as malaria is likely to
result in malaria over-diagnosis with consequent under-diagnosis of
other fever-causing disorders such as pneumonia.”
(Amexo et al. 2004. Malaria misdiagnosis: effects on the poor and
vulnerable)
1.) Discuss the challenge and problems of this issue.
2.) What do you consider the most ethical and cost-effective policy?

20. Discussion: Malaria misdiagnosis
“In a recent study of children reporting to health centres in Uganda,
Karin Kallander and colleagues found that 30% had symptoms
compatible with both pneumonia and malaria and required dual
treatment. This report, and previous studies, have concluded that
community treatment of all childhood fevers as malaria is likely to result
in malaria over-diagnosis with consequent under-diagnosis of other
fever-causing disorders such as pneumonia.”
(Amexo et al. 2004. Malaria misdiagnosis: effects on the poor and vulnerable)
Discuss the challenge and problems of this issue.
a) rapid, simple, accurate, inexpensive malaria diagnosis methods are not
widely available, particularly in poor communities where they are most
needed and individuals are least able to withstand the consequences of
the illness
b) how can one ensure that the more expensive combination therapies reach
most of those who truly have malarial illness and not just an elite
minority?
What do you consider the most ethical and cost-effective policy?
a) newer drug combinations used only for true cases of malaria
b) requirement: accurate malaria diagnosis

21. 30 %70 %
malaria
( = fever symptoms)
home treatment:
-traditional
remedies
-drugs from local
stores
health centres on
community level =
peripheral health facilities
Diagnosis:
solely based on clinical
features (i.e. fever)
bad quality diagnosis
pro: can reduce morbidity
contra: over-
diagnosis/over-treatment
of malaria as many
infectious diseases mimic
malaria pathology
health centres on district level =
district hospitals
Diagnosis:
1) Microscopy
- standard for malaria
diagnosis (accuracy 70-75%)
- challenge:
o well-maintained
equipment
o constant supply of
good-quality reagent
o trained staff:
monitoring,
supervising
2) Rapid Diagnostic Tests
- when microscopy unavailable
- based on detection of
Plasmodium specific proteins
- challenge:
o cost
o not quantitative =
inability to provide
information about
density of infection
o Not species specific:
can only diagnose P.
falciparum specifically
Design an educational step-
by-step plan for elucidating
locals about successful self-
treatment.

22. Proposal for educational self-
treatment plan
1) Discuss common errors concerning malaria
recognition
• i.e. false assumptions such as “malaria can be recognized from its
symptoms”
1) Advise that malaria presents in various ways
• i.e. differing malarial symptoms may mimic other diseases
1) Indicate need to seek professional medical care as soon
as possible
• i.e. self-treatment is a temporary, life-saving measure while
seeking medical attention or if medical care is not available
within 24h
1) Select self-treatment drug with care
• i.e. consider drug’s safety, efficacy, individual’s drug tolerance,
other medication etc.
1) Educate about drugs to avoid
• i.e. potential severe adverse effects and/or poor efficacy

23. Poor and Vulnerable less likely to seek modern medical care for treatment of fevers
- wait-and-see approach
- unaffordable fees
- long waiting lists
- unavailability of drugs
- poor attitude among staff
Misdiagnosis of Malaria =
contribution to a vicious cycle of increasing ill-health and
deepening poverty

24. Poor and Vulnerable less likely to seek modern medical care for treatment of fevers
- wait-and-see approach
- unaffordable fees
- long waiting lists
- unavailability of drugs
- poor attitude among staff
inaccurate diagnosis delayed diagnosis & treatment
Misdiagnosis of Malaria =
contribution to a vicious cycle of increasing ill-health and
deepening poverty

25. Poor and Vulnerable less likely to seek modern medical care for treatment of fevers
- wait-and-see approach
- unaffordable fees
- long waiting lists
- unavailability of drugs
- poor attitude among staff
inaccurate diagnosis delayed diagnosis & treatment
more prolonged and severe disease
Misdiagnosis of Malaria =
contribution to a vicious cycle of increasing ill-health and
deepening poverty

26. Poor and Vulnerable less likely to seek modern medical care for treatment of fevers
- wait-and-see approach
- unaffordable fees
- long waiting lists
- unavailability of drugs
- poor attitude among staff
inaccurate diagnosis delayed diagnosis & treatment
more prolonged and severe disease
Misallocation of Resources:
- underlying fatal conditions are masked
- exposure to unnecessary side-effects
- lost confidence in allopathic health services in favour of traditional healers
- lost productive time through illness (no insurance or savings)
- impacts on anyone: men, women, children (leave school to look after relatives  reduced
employment prospects
Misdiagnosis of Malaria =
contribution to a vicious cycle of increasing ill-health and
deepening poverty

27. Discussion: The long road to
malaria eradication
• We saw that poverty was a contributing factor to the misdiagnosis
of malaria, Peter Russell in 1946 wrote:
“but all the evidence we possess would seem to indicate not that
poverty is responsible for malaria but that malaria maintains
poverty” (Majori. 1999. The long road to malaria eradication)
With this in mind consider the following:
Three approaches have been identified in the fight against malaria:
– drug administration,
– vector control (insecticides or insecticide sprayed bed nets) and
– vaccine development.
Of these three which approach do you think is the most feasible?
Which would you allocate funds to?

28. Discussion: The long road to
malaria eradication
• The Director General of the WHO wrote to the 8th
World Health
Assembly:
“... At present time there are no obvious technical or economic reasons
why malaria could not be driven out of the Americas, Europe,
Australia and much of Asia within the next quarter of a century. As
regards tropical Africa the situation is not quite so promising…one
cannot foresee the elimination of malaria from Africa in the near
future”. (Majori. 1999. The long road to malaria eradication)
Do you agree or disagree with the latter part of this statement?
Why do you think the outcomes of malaria eradication differed
between countries of tropical Asia and countries of sub-Saharan
Africa?

29. Global distribution of malaria
Sachs and Malaney, 2002. The economic and social burden of malaria.

30. Global distribution of per capita
GDP
Sachs and Malaney, 2002. The economic and social burden of malaria.