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Malaria
Anders Björkman
1
Malaria – major public health problem
in the developing world
2
History
 Mal aria = bad air
 Romans
 Ancient Chinese and Indian medical texts
 Hippokrates 500 B.C
 Linnaeus 1735
 Laveran 1880
 Discovered the parasite in human blood (Nobel prize 1907)
 Ross 1898
 Described the complete life cycle in birds (Nobel prize 1902)
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What is Malaria?

Parasitic disease caused by
members of genus Plasmodium

>100 species described in
mammals, reptiles and birds

Five species infect humans





P. falciparum
P. vivax
P. ovale
P. malariae
P. knowlesi !!
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The species differ in: 1. morphology
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2. Differ in details of
their lifecycles.....
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3. Differ in clinical manifestations

Plasmodium falciparum
 Causes the most deadly and
severe infections.
 Infects all ages of erythrocytes
leading to a high parasitemia.
 Mature stages sequester in the
capillaries leading to symptoms.
 Widespread drug resistance.
 Incubation time ≥ 7 days
 Found in Tropics/Sub-Tropics
 Temperature 16-35oC
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 Plasmodium vivax
 P. vivax usually does not cause life-threatening infections.
 P. vivax only infects reticulocytes, gives low parasitemia
 P. vivax produces hypnozoites which are latent in the liver.
 Relapses can occur up to 5 years after infection
 P. vivax uses the Duffy blood receptor to enter erythrocytes
 P. vivax not found in West Africa.
 Found Temperate/Tropics/Sub-Tropics
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 Plasmodium ovale
 P. ovale resembles P. vivax in life cycle, appearance, clinical
presentation and treatment.
 However, can infect Duffy negative individuals.
 Found in Africa
2

Plasmodium malariae
 P. malariae usually does not cause life-threatening infections.
 P. malariae causes low grade parasitemia
 Description of parasite persistence > 40 years exists.
 Found in Tropics/Subtropics

Plasmodium knowlesi




Macaca monkeys natural host
Proposed as 5th human malaria parasite
Resembles P. malariae in microscopy
Can cause severe disease and death
 Found in South East Asia
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To complete the lifecycle
3 players are needed



Man = Host
Plasmodia = Agent
Female Anopheles mosquito = Vector
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Transmission
 By female Anopheles mosquito
 Endemic areas
 Local spread – airports
 Without mosquito
 Congenital
 Transfusion – accidental
 Controlled infection to treat other diseases, e.g. Neuro-syphilis
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Anopheles gambiae complex
 Most common vector of malaria in Africa
 General feeding habits:
 From dusk to dawn
 Other feeding preferences
 early evening - late at night.
 antropophilic (humans) - zoophilic (cattle)
 indoor (endophagic) - outdoor (exophagic)
 Resting place after blood meal
 Indoor (endophilic) or outdoor (exophilic)
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Malaria globally



2.5 billion people in >100 countries a risk (40% world population)
-300 million people experience clinical disease each year
-800 deaths each year
• 1 death every 45 seconds
• Majority of deaths are children >5 years and pregnant women in
sub-Saharan Africa
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Economic analyses indicate that
burden of malaria is enormous
 Highly malarious countries are among the poorest in the world
 Malaria obstructs economic development/growth
 Estimated annual loss of economic growth due to malaria 1.3%
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Malaria in Sweden





In whole of Europe below 2000 m altitude
Last case in Sweden 1933
Known as intermittent summer fever – “summer agues”
P. vivax – hypnozoites needed to survive the winter
5% of mosquito population Anopheles
 Malaria disappeared due to improved socio-economic standard
 Today imported malaria circa 100 patients/year
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Malaria epidemiology

Endemic: hypo (<10%), meso (11-50%), hyper (50-75%), holo (>75%)

Epidemic

Stable transmission
 Continuous exposure
 >10 infective mosquito bites per year (Entomological innoculation rate= EIR)
 Aquired immunity – small children + pregnant women affected

Unstable transmission
 Low EIR
 NO aquired immunity – all age groups affected
 Epidemic prone
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Clinical presentation:
fever most common symptom
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Uncomplicated vs. severe malaria syndrome
Criteria for severe malaria:
• Prostration
• Impaired consciousness
• Multiple convulsions
• Severe anaemia (Haemoglobin (Hb) <50 g/L)
• Hyperparasitaemia (>250 000/μL or >5% of red blood cells)
• Hypoglycaemia
• Respiratory distress (acidotic breathing)
• Pulmonary oedema (radiological)
• Circulatory collapse
• Abnormal bleeding
• Jaundice
• Haemoglobinuria
• Hyperlactataemia
• Acidosis
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Malaria Anaemia
 Hemolysis (both infected and non-infected RBCs)
 Removal by the spleen
 Bone marrow suppression
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ARDS
Cerebral
malaria
Severe
malaria
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Malaria immunity
Innate immunity
Sickle cell trait, Thalassemia trait, G6PD
Acquired immunity
“strain specific”
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P. falciparum in the African context
- the classical concept…..
 Fever in an African child = presumed to be malaria
 Problems
 Clinical diagnosis difficult
 Fever a cardinal symptom but not disease specific for malaria
 Fever overlaps with several other childhood illnesses, e.g.
respiratory tract infections, flu, meningitis, septicemia
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Malaria fever
“Musuja” (in Lugando) = fever = malaria
Now also “musuja from mosquito”
“Heev Taap” (in Maharas Iran/Bombay):
Shivering with cold - fever
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How to confirm a diagnosis of malaria?
 Microscopy
 Needs skilled technician, microscope, slides, staining material etc
 Time consuming but relatively cheep
 Detection limit under field conditions 50-100 parasites/ microlitre
 Rapid Diagnostic Tests (RDT)
 Relatively expensive
 Minimum training needed
 Can not quantify parasites
 Remains positiv after treatment – not monitor treatment outcome
 Sensitivity should be ≥95% for 100 parasites/mikrolitre blood
 Polymerase chain reaction (PCR)
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Microscopy
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RDT
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However, reality is often: No or limited
access to health care available..........
 A majority of fever sick children never reach formal health care
 Presumptive treatment given at home
 over/under diagnosis and treatment
 Treatment often not in correct dose/incomplete treatment course
 Drug resistance and increased morbidity & mortality
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The ears of the Hippopotamus…….
Breman 2001
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Causes of death in malaria
 Death within 24-48 hours after onset of disease common!
 Anemia (<2 years)
 Cerebral malaria (3-5 years)
 If surviving 5th birthday in high endemic area– decreased risk of
malaria associated death
 Protection against severe disease and death age dependent
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Malaria and co-morbidities
 Co-infections a reality in rural Africa
 Worm infestations, respiratory tract infections, septicaemia,
HIV/AIDS
 Measles, influensa – decreased risk?
 Malnutrition
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Driving forces behind drug development
Malaria:
 Major obstacle for expansion of colonial empires
 More lethal than bullets for soldiers in war
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Quinine - Jesuit’s Powder
 The drug that changed history!
 1628 Countess of Cinchon, ”fever tree bark”, Peruvian
Indians
 1643 Cardinal Juan de Lugo – promoted use in Europé –
”Jesuit’s bark”
 1747 Linnaeus named the tree Cinchona officinalis
 1820 Quinine isolated by Pelletier and Caventou
”Jesuit’s
 1854 large scale cultivation in Indonesia and India
 1914-18 Events during First World War indicated shortage of quinine
....................
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New drugs needed for new wars
 1934 German scientists developed chloroquine
 Second World War
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Development and spread of
chloroquine resistance
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US army starts to act....
 1967-74 New syntetic drugs under development
 1975 Mefloquine (Lariam®) introduced for treatment
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China strikes back.......



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Artemisia annua
Sweet Wormwood
Used for fever treatment
in China since ancient days –
340AD – Ge Hong
Modern use from 1979
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Driving force for drug development
 Not driven by the need of the poor in endemic areas
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Present drug policies
 Two outstanding antimalarial drugs are based on herbal
medicines
 Quinine
 Artemisinin-derivatives
WHO advocates combination therapy to
 Improve efficiacy
 Delay development of resistance
Artemisinin-based combination therapy (ACT)
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Artemisinin-based combination therapy
 Treatment of choice for uncomplicated malaria, but…..
 Much more expensive
 increased need for rational use
 and improved diagnostics
No syntetic artemisinin-derivative available on the market.......
http://www.who.int/malaria/docs/TreatmentGuidelines2010.pdf
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Artemisin based Combination Therapy
”ACT”
•
•
•
•
artemether + lumefantrine (Coartem/Riamet R)
artesunate + amodiaquine (Coarsucam R)
artesunate + mefloquine
dihydroartemisinin + piperaquine (Artekin)
•
artesunate + sulfadoxine/pyrimethamine
•
artesunate + pyronaridine (Pyramax)
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Treatment severe malaria

Artemisinin derivatives
 Artesunate (iv) for a total of 7 days, 2.4 mg/kg BW at 0h, 12h and
then once daily
 Artemether i.m.
 (Pre-referral administration of Rectocaps)

Quinine
 Loading dose 20 mg/kg in 5% dextrose over 4 hours
followed by 10 mg/kg x 3
 Treatment for 7 days
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Drug
Introduction
“First” year
resistance
reported
Difference
(years)
Quinine
Chloroquine
Proguanil
SulfadoxinePyrimethamine
Mefloquine
Atovaquone
Artemisinins
1632
1945
1948
1910
1957
1949
278
12
1
1967
1977
1996
1971
1967
1982
1996
2009
<1
5
<1
38
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Malaria in pregnancy

More sensitive to malaria compared to non-pregnant women
•
Women in first pregnancy in highly endemic areas have higher
risk for malaria parasitaemia compared to later pregnancies
•
Parasitized erythrocytes adhere to chondroitinsulfate A (CSA) in
placenta → accumulation of infected erythrocytes → chronic
inflammation
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Effects/risk of malaria in pregnancy

Maternal anemia and death
(responsible for 10 000
maternal deaths in Africa
annually)

Preterm labour and fetal growth
restriction resulting in low birth
weight (<2500 g)
(Responsible for 75000-200000
LBW yearly)

Stillbirth, abortion
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Interventions in pregnancy
 Insecticide treated nets (ITN)
 Intermittent preventive treatment (IPTp)
 Early access to prompt and effective treatment
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Intermittent preventive treatment (IPTp)

At least two separate doses of sulfadoxine-pyrimethamine (SP) in
second and third trimester given as a single dose under observation of
a health worker.

First dose when fetal movements are felt (18-20 weeks gestation) and
the second a month later.

HIV-positive women should receive three doses or all women if HIV
prevalence exceeds 10% and HIV testing is not available
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Effects of IPTp
 Clears infection, prevents clinical malaria and provides posttreatment prophylaxis
 Improves birthweight, reduces significantly the risk of low
birthweight, especially in primigravidae
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ITNs
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History of mosquito nets
 Bed nets made of silk were used by
the Chinese 1000 years ago
 A long tradition of mosquito net use is found in West-Africa, e.g.
Ghana
 DDT treated bed nets were first used during World War II
 Late 1970s synthetic Pyrethroids were developed to mimic
natural insecticidal compounds found in Chrysanthemums
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WHO starts to show interest in ITNs....

In the mid 1980s studies
confirmed the safety of using
pyrethroid insecticides to treat
nets and demonstrated
substantial effects on
entomological measures such
as EIR
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Untreated
vs Insecticide Treated Nets

Untreated Nets
 Protective barrier around persons using them
 Mosquitoes can feed on people through the nets or holes
 Efficacy data scarce, but probably effective

ITNs – enhanced efficacy
 Knock-down/lethal effect on insects
 Repellent

+ effect on other night biting insects
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Impact of ITNs on morbidity and mortality
 The initial reports led to Phase II and III clinical field trials, which
provided evidence that ITNs are successful in reducing both
 malaria morbidity (50%)
 all-cause child mortality (20%)
ITNs are important component of global and national
malaria control policies since the mid-1990s.
Recently Long lasting insecticidal nets (LLINs) with an effect up to
5 years are available and recommended
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Global strategies to fight malaria
 1955-70 Eradication
 Vertical program
 Lack of commitment and community participation
 Miss use of chloroquine – added in Salt etc
 Chloroquine and DDT resistance
Failed – malaria stroke back! !
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Modern malaria control strategies
 Early diagnosis and effective treatment with ACT
 Insecticide treated nets (ITN) or rather LLIN
 Indoor residual spraying (IRS)
 Intermittent preventive treatment (IPT - pregnancy/infants)
 Seasonal malaria chemoprevention (SMC – children)
 Improved diagnostics (Rapid Diagnostic Tests)
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Roll Back Malaria (Abudja, Nigeria, April 25, 2000)
 Halve the malaria mortality for Africa's people by 2010,
through implementing the strategies and actions for Roll Back
Malaria
 >60% of malaria patients should access correct, affordable and
appropriate treatment within 24 hours
 >60% at risk, children <5 and pregnant women, to sleep under
Insecticide treated nets (ITP)
 >60% of pregnant women should have access to Intermittent
Preventive Treatment (ITPp)
 The above targets have later been revised to 80%
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Millenium Development Goals
1.
2.
3.
4.
Eradicate Extreme Poverty and Hunger
Achieve Universal Primary Education
Promote Gender Equality and Empower Women
Reduce Child Mortality
Reduce by two-thirds, between 1990 and 2015, the under-five mortality rate
5. Improve Maternal Health
6. Combat HIV/AIDS, Malaria and other Diseases
Halt and begin to reverse the incidence of malaria and other major diseases
7. Ensure Environmental Sustainability
8. Develop a Global Partnership for Development
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Is there hope for Africa in the
battle against Malaria??




Malaria is on the agenda!
Commitment higher from leaders
International initiatives/collaborations – Global Fund
New donors - Bill and Melinda Gates
 Combined interventions giving positive results – e.g. Zanzibar
 Sustainability? Elimination?
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………an emerging threat against
global malaria control……..
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Remember the history of development and spread
of chloroquine resistance………
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