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Malaria

INFECTIOUS DISEASE
EPIDEMIOLOGY
Malaria

HISTORY
Another ancient infection: interaction and co-
evolution of vertebrates, mosquitoes and
Plasmodium is tens of thousands of years old
Documentation of malaria:
2700 BC in China
Homer, Plato, Aristotle, all describe malaria
1902 Ronald Ross describes how malaria is
caused by a protozoan parasite that infects the
red blood cell and is transmitted by mosquito
Malaria

HISTORY
Incan civilization treatment for malaria:
cinchona bark (quinine)
Greeks recognize the importance of low-lying
water and swamps in control efforts
World War II
Dichlorodiphenyltrichloroethane
Chloroquine replaced quinine as main anti-malarial
drug
Malaria

PUBLIC HEALTH SIGNIFICANCE


The impact of malaria varies tremendously in
different parts of the world
While each of the four species of Plasmodium
that are relevant for human infection can cause
disease burden, Plasmodium falciparum is
associated with the greatest morbidity and
mortality
The region most affected is the tropical belt of
Africa
Malaria
PUBLIC HEALTH SIGNIFICANCE
Incidence and resulting disability and mortality
determine any diseases public health
significance
However, given the greatly varying endemicity in
different geographic locations, and given the
role played by the level of endemicity in clinical
disease, incidence is not always a useful metric
It can be useful in areas of low to moderate
transmission
It is virtually useless in areas of high or very high
transmission (holoendemicity)
Malaria
PUBLIC HEALTH SIGNIFICANCE
1 to 2 million children die each year from
malarial disease
~ 1 million deaths have been reported on an
annual basis by WHO since the 1950s
About 90% of these deaths occur in Africa
In Africa, malaria is one of the greatest causes
of mortality in infants and children, and of
disability in adults
Malaria

The Parasites and the


Life Cycle
Malaria-The Parasites and the Life Cycle
Four species of protozoan parasite of the genus
Plasmodium that are relevant for human infection
P. falciparum
P. vivax
P. ovale
P. malariae

P. vivax is the most widespread malaria infection in


the world
P. falciparum causes the most severe malaria
disease in the world and is responsible for the
most deaths and morbidity
Plasmodium Life Cycle
The parasite undergoes several
transformations with both the human host
(intermediate) and mosquito host (definitive)
Transmitted to humans as sporozoites from
the saliva of an infected female mosquito
Sporozoites enter the venous blood system
from the subcutaneous tissues by way of the
capillary bed and can invade liver cells within
minutes if they successfully evade the
reticuloendothelial defenses
Plasmodium Life Cycle

Over the next 5 to 15 days, each sporozoite


nucleus replicates thousands of times within
the liver cells to form a hepatic schizont
within the liver cells
When released from the swollen liver cells,
each schizont splits into tens of thousands of
daughter parasites called merozoites
Merozoites attach to specific erythrocyte
receptors and enter the erythrocyte
Plasmodium Life Cycle

Each intraerythrocytic meroziote differentiates


into a trophozoite that ingests hemoglobin,
enlarges, and then divides into 6 to 24
intraerythrocytic merozoites forming a schizont
The red cell swells and bursts, which releases the
next batch of approximately 20 merozoites
Theses new merozoites then attach and
penetrate new erythrocytes to begin the cycle
again
Plasmodium Life Cycle
Along with the liberation of the merozoites from the ruptured erythrocytes, the
resultant lysis and release of pyrogens from the infected RBCs and the hosts
response to these toxins correspond with the clinical paroxysms of fever and
chills
The simultaneous release from many RBCs accounts for the periodicity of these
symptoms observed in many patients
This second stage of asexual division takes 48 hours for P. falciparum, P. vivax,
and P. ovale, and 72 hours for P. malariae
A single P. falciparum merozoite can potentially lead to 10 billion new parasites
through these recurrent cycles
After a number of cycles within the RBCs, some merozoites differentiate into
gametocytes (macrogametocytes are female and microgametocytes are male)
that can then be ingested by the mosquito during the next blood meal
Plasmodium Life Cycle
Sporogonic Development
Once in the mosquito, the RBCs are digested, which frees the
gametocytes and they then begin sexual reproduction
The male and female gametes fuse, thus forming the zygote
During the next 12 to 14 hours the zygote elongates and forms an
ookinete, which in turns seeks out and penetrates the wall of the
mosquitos stomach where it will become an oocyst
During the next several days, the oocyst swells as it forms more than
10,000 sporozoites
After the oocyst ruptures the sporozoites migrate to the salivary
glands where they are ready to be reintroduced to humans during the
next blood mean, thus completing the life cycle
Plasmodium Life Cycle
Sporogonic Development
This phase of the life cycle, from ingestion of gametocytes to the point when
salivary sporozoites are ready for human infection takes about 7 to 12 days
The time required depends on the Plasmodium species as well as temperature
and humidity:
Higher temperature and higher humidity decrease the duration of
development
Lower temperature can extend the period required (e.g. 23 days for P.
falciparum at 20 degrees C)
Given the average lifespan of anopheline mosquitos is less than three weeks,
temperature is critical for sporogonic (extrinsic) period of the parasites
lifecycle
Plasmodium Life Cycle

Biologic Differences Among Plasmodium Species


With P. vivax and P. ovale, some sporozoites entering the hepatocytes do not
immediately proceed to tissue schizogony
Those that dontbecome hypnozoites and can lie dormant for months to
years
Later these hypnozoites can differentiate and become hepatic schizonts,
leading to the cycle of erythrocytic schizogony and relapse symptoms
This biologic variant accounts for the relapses characteristic of P. vivax and P.
ovale and requires specific drug treatment to target the hypnozoite stage
Plasmodium Life Cycle

Biologic Differences Among Plasmodium


Species
P. falciparum does not produce hypnozoites
and so does not exhibit relapse following
effective treatment
However, ineffective treatment can result in
persistent low-grade parasitemia, which can
lead to recrudescent clinical malaria
Distinguish between relapse and
recrudescence
Plasmodium Life Cycle

Biologic Differences Among Plasmodium Species


Different species have different affinities for
different types of erythrocytes
P. vivax and P. ovale only invade the young
reticulocytes, thus the density of peripheral
parasitemia in these infections rarely exceeds 3%
P. malariae prefers older RBCs
P. falciparum infects erythrocytes of all ages, and
so is able to produce high density parasitemias
with serious morbidity and high mortality
Plasmodium Life Cycle
Biologic Differences Among Plasmodium Species
Gametocyte production varies by species
After infection with P. vivax, gametocytes appear in the
peripheral blood almost as soon as the asexual erythrocytic stage
begins
Gametocytes are usually present when vivax malaria is diagnosed
and before antimalarial Tx has begun
P. vivax can be transmitted prior to symptomatic disease, so its
gametocytes will not have been exposed to drug pressure that
would select for drug-resistant mutants
Therefore, drug sensitive parasites are not at a competitive
disadvantage with drug resistant strains
Plasmodium Life Cycle
Biologic Differences Among Plasmodium Species
Gametocyte production varies by species
Following infection with P. falciparum, gametocytes appear only after several
intraerythrocytic cycles, first appearing at least 10 days after the appearance of
clinical disease
Early Tx of P. falciparum with an effective drug will kill blood stage schizonts,
preventing gametocytes from developing and thus blocking transmission
However, gametocytes that do develop will be derived from parasites that
survived treatment and may then carry drug resistance
This strongly assists the selection of drug resistant parasites
P. falciparum demonstrates much greater drug resistance than does P. vivax
Malaria
Anopheline Mosquitos and Their Life Cycle
Malaria (in humans) is transmitted by
mosquitoes of the genus Anopheles
70 species are capable of transmitting human
malaria, but only about 40 are important
vectors
Anopheline mosquitoes are vegetarian!
The female anopheline requires protein derived
from host blood for her egg production, thus
only the female is the vector for malaria
Anophelines and Their Life
Cycle
There is great variation among species in host feeding
preference, biting and resting behavior, and in the selection of
larval habitat for laying the eggs
Some anophelines are zoophilic and will take blood from a
variety of vertebrates, whereas others are very particular and
will only take the meal from humans (anthropophilic)
Some are endophagic, taking blood only indoors, while others
are exophagic, taking the meal outdoors
Endophilic resting (indoors) versus exophilic resting (outdoors)
after taking blood is very important in different approaches to
malaria control
Anophelines and Their Life
Cycle
There is great variation among species in host feeding
preference, biting and resting behavior, and in the selection of
larval habitat for laying the eggs
Almost all anopheline mosquitoes prefer clean water in which
to breed, but different species have very specific preferences
in the aquatic environment for laying eggs
A. stephensi breeds in tin cans and confined water systems
A. gambiae prefers small, open sunlit pools
Understanding water preferences is also critical in approaches
to vector control
Anophelines and Their Life
Cycle
Four stages of growth during Anopheles life
cycle
Egg > Larva > Pupa > Adult
Anophelines and Their Life
Cycle
Shortly after emerging as an adult, and before the first blood
meal, adult anopheline females mate
Typically mate once, storing sperm and laying a total of 200 to
1000 eggs in 3 to 12 batches over their adult lifetime
A fresh blood meal is required for the development of each egg
batch
After hatching, the larva feed at the waters surface and develop
over 5 to 15 days before pupating
The adult mosquito then emerges within 2 to 3 days
The total cycle requires 7 to 20 days depending on the
anopheline species and the environmental conditions
Anophelines and Their Life
Cycle
With favorable humidity and temperature,
anopheline mosquitoes can survive for a
month or longer
Plenty of time to complete the 7 to 12 days
sporogonic cycle
When the sporogonic cycle is complete, the
mosquito is capable of infecting the human
host with each subsequent blood meal, which
is often taken every 2 to 3 days for the
remainder of the mosquitos life
Anophelines and Their Life
Cycle
Anopheline mosquitoes seek out their host
using a combination of chemical and physical
stimuli:
Carbon dioxide (follow the gradient)
Body odors
Heat (follow the gradient)
Movement
Most anophelines feed at night, but some
may feed in the dusk of morning or evening
Anophelines and Their Life
Cycle
During feeding the mosquito injects enzymes in
her saliva into the subcutaneous tissue
These enzymes diffuse through the surrounding
tissue and facilitate both the acquisition of blood
(increasing blood flow) and the transfer of
sporozoites to the capillary bed
After feeding the engorged female must rest (24
to 36 hrs), typically on a nearby wall or secluded
spot outside
After the resting period the female then
searches out a site for oviposition
Malaria
Entomological Inoculation Rate (EIR)
The EIR is the number of infected bites that each person
receives per night
EIR = (HLR) X (SR)
HLR = human landing rate is the number of mosquito
landings (bites) per night
This number is obtained by capturing all mosquitoes that land on a
person
SR = ratio of infected anophelines to the total captured
Determined by microscopic examination of dissected salivary glands to
detect sporozoites
Serologic and molecular techniques have now been developed to
measure the SR
EIR provides a direct measure of malaria transmission and the risk
of human exposure to the bites of infected mosquitoes
Malaria
Vectorial Capacity
Measures the rate of potentially infective contact, i.e. potential
for malaria transmission
Based solely on key vector parameters in a given area
VC = ma2pn/-logp
m is the density of vectors in relation to humans
a is the human biting habit (proportion of blood meals taken from
humans to the total number taken from any animal)
A person is bitten by ma vectors in 1 day
p is the daily survival probability of the vector
n is the extrinsic incubation (sporogonic) period
pn are the vectors that survive the extrinsic cycle
1/-logp is the daily expectation of life: each surviving vector bites
a persons/day
Malaria

Vectorial Capacity
So, VC is the number of potentially infective
contacts an individual human could acquire in
a given area, through the vector population,
per unit of time
In theory, the VC can predict the extent to
which anopheline populations must be
reduced in order to reduce transmission
Non-linear relationship between VC and
parasitemia
Malaria

Geographic Areas by Transmission Intensity


Holoendemic:
Areas of intense transmission with continuing
high EIRs, where virtually everyone is infected
with malaria parasites all the time
In older children and adults, detection of
parasites may be difficult because of immunity,
but sufficient searching should reveal their
presence
Classification on the basis of children under age
10: spleen and parasitemia rates over 75%
Malaria

Geographic Areas by Transmission Intensity


Hyperendemic
Areas with regular, often seasonal,
transmission, but where immunity in some of
the population does not confer protection at
all times
Classification on the basis of children under
10: spleen and parasitemia rates from 50% to
75%
Malaria

Geographic Areas by Transmission Intensity


Mesoendemic
Areas that have malaria transmission fairly
regularly, but at much lower levels
The danger in these areas is occasional
epidemics involving those with little immunity
and resulting in fairly high morbidity and
mortality
Classification on the basis of children under 10:
spleen and parasitemia rates ranging from 10%
to 50%
Malaria

Geographic Areas by Transmission Intensity


Hypoendemic
Areas with limited malaria transmission and
where the population will have little or no
immunity
Classification based on children under 10:
spleen and parasitemia rates less than 10%
These areas can also have severe malaria
epidemics involving all age groups
Malaria
Further Classification (1990 WHO)
Eight major malaria paradigms intended to
categorize typical transmission settings
Malaria of the Africa savannah
Forest malaria
Malaria associated with irrigated agriculture
Highland fringe malaria
Desert fringe and oasis malaria
Urban malaria
Plains malaria
Seashore malaria
Malaria - Pathogenesis
Infection and Disease
Infection with Plasmodium does not necessarily result in
disease, especially in highly endemic areas
In these areas, children may have parasitemia prevalence of 50% or
more, and yet few will demonstrate symptoms
However, P. falciparum malaria infection in children can
range from asymptomatic to severe overwhelming
disease and rapid death
Can present with drowsiness, coma, convulsions, or simply
listlessness and fever with nonspecific symptoms
Abdominal cramps, coughs, headaches, muscle pains, and
varying levels of mental disorientation are also common
Severe and complicated malaria due to P. falciparum is a
medical emergency
Malaria - Pathogenesis
Host Response
Malaria on a population basis is the most intense
stimulator of the human immune system known
Reticuloendothelial system with enhanced phagocytosis
in the spleen, lymph nodes and liver to remove infected
RBCs
Intense production of antibodies (several g/L of Ig against
malaria)
A range of cell-mediated immune responses
Cytokine cascades
For example, pro-inflammatory cytokines, severe
metabolic acidosis, and the classical sequestration of
infected RBCs (causing cerebral anoxia) all may
contribute to the pathogenesis of cerebral malaria
Malaria - Pathogenesis
Host Response
Tropical slpenomegaly
Fairly common among relatively nonimmune populations
(become exposed because they move, or because of a
change in climate)
Begins in childhood and progresses through adolescence
to young adulthood with:
Severe anemia
High levels of IgM and anti-malaria antibodies
Decrease in platelets
Enlarged spleen
Parasites are rarely detectable
If untreated it is often fatal, usually due to secondary
infection
Malaria - Pathogenesis

Host Response
Plasmodium parasites have evolved many
complex mechanisms to evade the host immune
response and establish persistent or repeated
infection
As such, protective immunity following natural
infection takes many years to develop
No immunodominant response has been
identified and so an effective immune response
is likely the sum of cellular and humoral
responses to multiple parasite antigens
Malaria - Pathogenesis

Host Response
Antibodies to the circumsporozoite protein can
prevent the sporozoites from binding to liver
cells
Cellular immune responses, in particular
interferon gamma producing T cells, are
important in killing infected liver cells
Both humoral and cell-mediated immunity play
roles in killing parasitized RBCs
Antibodies to erythrocytic stages may act
through monocytes in a process called antibody-
dependent cellular inhibition
Malaria - Pathogenesis

Undernutrition and Micronutrient


Deficiencies
Malaria is prevalent in areas where childhood
malnutrition is common
Nutritional deficiencies interact with malaria
infection
Malaria - Pathogenesis

Undernutrition and Micronutrient Deficiencies


Protein-energy malnutrition (PEM): a group of
related disorders that include marasmus,
kwashiorkor, and intermediate stages
Marasmus:
Inadequate intake of protein and calories
Deficient in all nutrients
Essentially starvation
Characterized by emaciation
Kwashiorkor:
Inadequate protein intake, but with reasonable caloric
(carbohydrates) intake
Characterized by edema
Malaria - Pathogenesis

Undernutrition and Micronutrient Deficiencies


All forms of PEM impair the functioning of all
body systems and particularly cellular and
humoral immunity
Recent evidence demonstrates that
malnourished children are more likely to die
from malaria than adequately nourished children
Malaria prophylaxis should be provided to
malnourished children in malaria areas when
treating PEM
Malaria - Pathogenesis
Undernutrition and Micronutrient Deficiencies
Iron deficiency is the most common
micronutrient deficiency and is associated with
defects in the immune response and poor health
outcomes
However, iron supplementation may increase the
level of parasitemia (significant) and clinical
attack rates (not significant)
Nevertheless, iron supplementation reduces the
risk of severe anemia in malaria by 50% and
therefore outweighs the potential increase in
parasitemia since this increase is not associated
with increases in severe malaria
Malaria - Pathogenesis

Undernutrition and Micronutrient Deficiencies


Vitamin A is essential for proper immune
function
Supplementation can reduce clinical attack rates
(number of clinical episodes), splenic
enlargement, and parasetemia
Most relevant for young children
Fraction of malaria morbidity attributable to
Vitamin A deficiency may be as high as 20%
worldwide
These are based on very limited data
Malaria - Pathogenesis

Undernutrition and Micronutrient


Deficiencies
Zinc is also essential for proper immune
function, both humoral and cell-mediated
Zinc supplementation reduces clinical attack
rates, especially attacks with high density
parasitemia
Fraction of malaria morbidity attributable to
zinc deficiency may also be as high as 20%
worldwide
Falciparum Malaria Disease
Severe Malaria
Disease caused by P. falciparum is a major cause of death
in children wherever there is a high intensity of infection
Malaria may account for half the mortality rate for
children under 5 years old in holoendemic areas
In holoendemic areas severe disease in children does not
progress from mild or moderate illnessit strikes abruptly
without warning
Mothers often cannot get their infants and young children
to a health center in time for Tx before the child dies (even
in the presence of readily available facilities)
Rapid progression to severe disease is not characteristic in
areas with less intense transmission
Falciparum Malaria Disease
Severe Malaria
In South and Southeast Asia, malaria typically
progresses in severity over several days in both children
and in adults in both major forms of severe disease that
occur there:
Cerebral malaria (median time of 5 days from onset to
cerebral symptoms) and multiple organ dysfunction
syndrome (MODS) (median time of 8 days)
Early effective Tx before the onset of the severe phase is
the key to reducing mortality
The slow progressing form is much less common in
holoendemic areas and therefore less common in much
of Africa
Falciparum Malaria Disease
Clinical Patterns
WHO Criteria for severe malaria 1990
Coma
Severe anemia
Respiratory distress
Hypoglycemia
Circulatory collapse
Renal failure
Spontaneous bleeding
Repeated convulsions
Acidosis
Hemoglobinuria
Addition WHO criteria for severe malaria 2000
Impaired consciousness
Prostration
Hyperparasitemia
Hyperpyrexia
Hyperbilirubinemia
Falciparum Malaria Disease
Clinical Patterns
Most children presenting with severe malaria can be
placed in 1 of 3 distinctive syndromes:
2 syndromes that are readily delineated clinically
when the child is first seen:
Neurologic deficit about 20% of hospital
admissions with about 15% case fatality
Respiratory distress about 14% of admissions also
with about 15% case fatality
The third, also life-threatening syndrome, is not so
readily apparent clinically
Severe anemia about 18% of admissions with
about 5% mortality
Falciparum Malaria Disease

Clinical Patterns
Hypoglycemia and metabolic acidosis are
central in the pathogenesis of severe malaria
Hypoglycemia has been estimated at about
14% prevalent (similar to respiratory distress)
with 22% case fatality
Falciparum Malaria Disease
Cerebral Malaria
Histopathologically due to the massive sequestration of
infected cells in the cerebral microvasculature
Case-fatality ranges from 10% to 50%
CM is heterogeneous with 4 overlapping syndromes with
different pathogenic mechanisms
Prolonged postictal state, characterized as deep sleep,
headache, confusion and muscle soreness
Covert status epilepticus, characterized by continual
seizures
Severe metabolic derangement, particularly with
hypoglycemia and metabolic acidosis
Commonly more than 1 coexist, and recognition and
management of all, plus malaria Tx, must be
implemented
Falciparum Malaria Disease
Respiratory Distress
Pulmonary edema, often seen with acute respiratory
distress syndrome has long been recognized as a
serious, often fatal, complication of malaria
Respiratory distress is a valuable defining
characteristic because the clinical signs can be applied
with good interobserver consistency, and with
minimal training
The clinical signs of hyperventilation (driven by efforts
to reduce CO2) are highly sensitive and specific for the
diagnosis of respiratory distress
Falciparum Malaria Disease

Respiratory Distress
Cardiac failure, coexisting pneumonia, direct
sequestration of malaria parasites in the
lungs, and increased central drive to
respiration in association with cerebral
malaria, all contribute to respiratory distress
Main factor is metabolic acidosis largely due
to lactate production caused by reduced
oxygen to the tissues
Falciparum Malaria Disease

Severe Anemia
Complex pathogenesis and varies greatly
geographically because of its interaction with
PEM and iron deficiency
Tends to be the predominant form of severe
malaria in areas of the most intense transmission
and is common in the youngest age groups
Malnutrition, anemia and dehydration influence
the Tx and expected outcomes of severe malaria
Malnourished children are at increased risk of
death from malaria
Falciparum Malaria Disease

Epidemiologic Features of Severe Malaria


As the intensity of transmission increases, the
proportion of the population with severe
malaria shifts to the younger age groups
In areas with the most intense transmission,
severe malaria and death are typically
restricted to children younger than 5 years,
and most clinical disease occurs in the those
younger than 10 years
Falciparum Malaria Disease

Epidemiologic Features of Severe Malaria


In endemic areas, the pattern of severe
morbidity varies with age
Severe anemia predominates in younger
children (median age 15 to 24 months)
Coma is more common in older children
(median age 36 to 48 months)
Falciparum Malaria Disease
Epidemiologic Features of Severe Malaria
However, across endemic areas of different levels of
transmission intensity, there can be marked differences
in the age distribution of children with severe malaria
and in the relative importance of different clinical
syndromes
For example
EIR = 100 bites/year: severe malaria presents more commonly
as severe anemia at younger ages
EIR = 10 bites/year: severe malaria presents more commonly as
cerebral symptoms at an older age
Also, constancy of transmission is important:
Intense perennial transmission is associated with severe
anemia in severe malaria
Intense seasonal transmission is associated with cerebral
malaria in severe malaria
Falciparum Malaria Disease

Epidemiologic Features of Severe Malaria


In most child deaths in tropical Africa malaria
is a contributing factor even though death
may be attributed to another cause such as
diarrhea or pneumonia
When malaria is controlled in holoendemic
areas, a major reduction in overall child
mortality follows
Falciparum Malaria Disease

Malaria in Pregnancy
Women infected with malaria while pregnant
are at much greater risk of serious disease
and complications than women who are not
pregnant or men
Host defense mechanisms to malaria are
greatly diminished during pregnancy and for
several weeks postpartum with reductions in
both cell-mediated and humoral responses
Falciparum Malaria Disease
Malaria in Pregnancy
In all areas endemic for malaria, pregnant women
are more likely to be bitten by malaria vectors
Higher metabolic rate in pregnancy:
Increases body temperature
Increases CO2 release
Can also be behavioral
E.g., pregnant women who have to leave home in the night
more frequently to urinate
Pregnant women are at higher risk of infection with
all Plasmodium species, and are at increased risk for
all malaria types
At higher risk for severe, complicated malaria and
death
Falciparum Malaria Disease

Malaria in Pregnancy
The maternal mortality rate ranges from 100
to over 1000 per 100,000 live births
This MMR is the same in low and high
transmission areas
However, the nature of the complications is
different, as are those at risk (e.g. first
pregnancies)
Falciparum Malaria Disease
Malaria in Pregnancy
In low transmission areas, pregnant women across
the spectrum of parity die from severe complicated
malaria particularly with cerebral symptoms,
hypoglycemia and acute respiratory distress
syndrome: MMR up to 1000 per 100,000 live births
In high transmission areas, the risk of severe disease
and death is mainly due to severe anemia and
mainly occurs among women in their first
pregnancy, even though they had a high level of
immunity prior to becoming pregnant: MMR over
1000 per 100,000 live births
Falciparum Malaria Disease
Malaria in Pregnancy
Adverse outcomes of the pregnancies are higher in
women with malaria because of active malaria
infection of the placenta
Effects of both past and present placental infections
combined with the often-intense host responses
contribute to the high fetal losses associated with
malaria
First pregnancy versus subsequent
Uterine immunology is nave relative to the mothers otherwise
systemic immune responses
Falciparum Malaria Disease
Malaria in Pregnancy
Higher rates of low weight births and still births
Low birth weight is increased in both low and high
transmission areas, but for different reasons:
Low transmission areas have more pre-term delivery
High transmission areas have more fetal growth
retardation
Higher rates of perinatal and infant mortality (follows
from the above)
Falciparum Malaria Disease

Malaria in Pregnancy
Population Attributable Risk:
Low birth weight: 8% to 14%
Pre-term delivery: 8% to 36%
Fetal growth retardation: 13% to 70%
Infant mortality: 3% to 8%
Falciparum Malaria Disease

Malaria in Pregnancy
The greatest risk is associated with malaria
infection is in the second and third trimester
Reduction of infection in the 2nd and 3rd
trimesters dramatically reduces the severe
consequences associated with malaria in
pregnancy (though not to the level of areas
with no malaria)
Malaria Human Activities
and Epidemiology
Agricultural development, population
movement, and urbanization are important
determinants of the pattern of malaria
transmission
Malaria Human Activities
and Epidemiology
Agriculture
Malaria has long been linked to farming practices
In sub-Saharan African, the clearing of forest for crop
production has lead to increased breeding Anopheles
gambiae
The most efficient vector of human malaria
Prefers sunlit open pools of standing water to the full shade of
tropical forest
The formation of small towns, dams and irrigation
systems arising in concert with agricultural development
has concentrated humans and vectors in relatively
confined areas near water sources
Agricultural use of pesticides has led to insecticide-
resistant vectors
Malaria Human Activities
and Epidemiology
Population movement
Traditionally, in many parts of Africa seasonal
migration has been a part of life with people
moving from village settlements to rural farms
during the early months of the wet season
Often the intensity of transmission is much
higher in these areas than in their settled villages
where water supplies are controlled
Also, many pastoral people are exposed to areas
of high transmission as they move their livestock
from highland to lowland pastures with the
seasons
Malaria Human Activities
and Epidemiology
Population Movement
Drought, famine and conflict lead to massive
population displacement and refugee
movements
Movements often from more settled areas to
fringe areas
These groups are typically poorly served by
government health and malaria control
programs, and have minimal access to
antimalarial drugs and other health care needs
All of these contribute to increased malaria
transmission
Malaria Human Activities
and Epidemiology
Population Movement
The majority of modern migration is to urban areas
This migration trend has less effect on the
transmission of malaria, because malaria, especially
in Africa, is primarily a rural rather than an urban
disease
However, some anopheline species have become
well adapted to the urban environment (A.
arabensis)
Urban anophelines are typically restricted to semi-
urban slum areas, rather than concentrated city
centers
Malaria Human Activities
and Epidemiology
Socioeconomic Status
Malaria can strike in anyone, but it is
principally a disease of the poor
Loss of healthy life due to malaria is much
higher in poor rural areas
There is even strong biologic evidence of this:
the distribution of sickle trait is significantly
higher in rural children not attending school,
than in those children from developed urban
areas attending good schools
Malaria Human Activities
and Epidemiology
Health Seeking Behavior
Importance of cultural practice and beliefs
Importance of misunderstanding the
symptoms of cerebral malaria because of
convulsions and confusion
Malaria Diagnosis and
Treatment
A definitive diagnosis is made by
demonstration of parasites in red blood cells
Gold standard technique is microscopic
examination of Giemsa-stained thick and thin
smears of blood (thick smear is more
sensitive)
Malaria Diagnosis and
Treatment
Problems with Blood Smears -
Implementation
Work is very tedious and requires continuous
concentration
Delays in viewing smears result in delays in Tx
Maintenance of the microscope and staining
materials requires rigorous control
Training technicians and monitoring their
work requires sustained effort
Malaria Diagnosis and
Treatment
Problems with blood smears Interpretation
Peripheral smears may be falsely negative before
RBCs are infected and later during schizogony when
infected RBCs are sequestered in the capillary beds
The peripheral smear may be falsely positive
because the presence of parasites in a blood smear
from a febrile patient in an endemic area does not
necessarily mean that the symptoms are due to
malaria
Most school-age children in holoendemic areas are
parasitemic all the time, so there is no specific
approach to diagnosing clinical disease in this setting
Malaria Diagnosis and
Treatment
Treatment History
Cinchona bark used by Incas and Peruvians for
thousands of years
This was brought back to Europe in the 17th
century by Jesuit missionaries
In 1820 the active ingredient was identified as
the alkaloid quinine (still an effective agent
against drug-resistant falciparum malaria)
Chloroquine was synthesized in the late 1930s in
Germany. During World War II it was captured
and recognized to be highly effective against
malaria
Malaria Diagnosis and Treatment
Treatment Chloroquine
Rapidly absorbed after oral administration
Active against the asexual stages of all human species
except for strains of P. falciparum that have become
resistant
Interferes with the degradation of heme, which allows the
accumulation of toxic metabolic bi-products (heme
molecules from the hemoglobin) and kills the parasite
within the RBC
In appropriate doses, chloroquine is well tolerated even
when taken for long periods and is safe for young children
and pregnant women
Because of low toxicity, low cost, and effectiveness this
was the malaria drug of choice for decades following
World War II
Malaria Diagnosis and Treatment
Treatment Primaquine
Developed by the US Army during World War II
The only drug effective against sporozoites and the
hepatic forms:
Thus, it can be used to prevent infection in the liver
(known as causal prophylaxis)
It can also be used to eliminate the hypnozoite stage of P.
vivax and P. ovale (anti-relapse treatment)
The drug is also effective in eliminating gametocytes:
Theoretically it could play a role in reducing transmission
and preventing the spread of drug resistant strains
However, primaquine does cause hemolysis in people with
glucose-6-phosphate dehydrogenase deficiency, which is
common in those of Mediterranean and African descent
Malaria Diagnosis and Treatment
Treatment Sulfadoxine-pyrimethamine
Originally developed for its efficacy against
chloroquine-resitant P. falciparum
Has been widely used to replace chloroquine in areas
of drug resistance
Because it is single-dose therapy and inexpensive, SP
is widely used in Africa to treat malaria
This is the preferred antimalarial for pregnant women
Can be used for intermittent prophylactic treatment
of young children
There can be some adverse reactions (Stevens-
Johnson syndrome) when used for prophylaxis
Malaria Diagnosis and
Treatment
Treatment
Chloroquine and SP have been the most
commonly used drugs to treat malaria in
Africa, but widespread drug resistance has
significantly reduced their effectiveness
Malaria Diagnosis and
Treatment
Treatment Mefloquine
Developed in the late 1960s by the US Army for
its activity against chloroquine resistant P.
falciparum
Used for prophylaxis and for treatment in
combination with artesunate in Southeast Asia
Resistance to mefloquine has now emerged in
Southeast Asia
Frequent reports of adverse mental reactions
have led to reduction in its use in general
Malaria Diagnosis and
Treatment
Treatment Artemisinin (and related compounds
artesunate, arthemether)
The active agent of the Chinese herbal medicine
(Artemisia annua)
Inhibits the P. falciparum ATP6, a calcium-pumping
enzyme
The drugs quickly clear blood stage parasites and
gametocytes
Provide a rapid clinical response
Resistance to artemisinins has not been observed yet
However, when used alone, recrudescence is common
so these are usually combined with other antimalarials
Malaria Drug Resistance
The emergence and spread of drug-resistant malaria,
particularly chloroquine and sulfadoxine-pyrimethamine-
resistant P. falciparum, are of major public health importance
and likely responsible for the doubling of child mortality
attributable to malaria in parts of Africa
Once highly effective, safe and affordable drugs, they have been
rendered useless in many malaria endemic regions, forcing
countries to use more expensive artemisinin-based combination
therapies
Resistance to more recently introduced antimalarials, like
mefloquine, developed very fast
It may only be a matter of time before resistance develops to the
atremisinins, but their short half-life and their ability to reduce
gametocyte carriage has likely been responsible for the delay of
such resistance
Drug resistance is largely associated with P. falciparum (though
some chloroquine resistant P.vivax exists in PNG).
Malaria Drug Resistance
Contributing factors
Pharmacologic properties of the drug:
Prolonged half-life
Poor compliance
Inappropriate use
All these can cause the parasites to receive subtherapeutic
drug levels
Host immunity:
Relevance of immunologically nave hosts
Parasite genetics antigenic variation
Transmission characteristics:
Level of endemicity
Species of mosquito and its behavior
Malaria Drug Resistance

Assessing Drug Resistance


Evaluation of therapeutic responses in vivo
Measurement of parasite growth ex vivo
Identification of genetic mutations associated
with resistance
Malaria Drug Resistance
Assessing Drug Resistance in vivo
Traditional in vivo testing developed by WHO
Infected patients are given an antimalarial drug according
to an established regime
Parasite counts are made at the start of therapy, at 24
hours, at 7 days and at 28 days after the start of Tx
If parasites are not detected at the end of 7 days (and still
not at 28 days) the parasites are considered sensitive
If there is clearance of parasites at 7 days but
recrudescence at 8 or more days after the start of Tx, the
parasites are stage RI resistant
If there is reduction in parasitemia but not complete
clearance at 7 days, the parasites are considered stage RII
resistant
If there is no evidence of response, the parasites are
considered fully resistant, stage RIII
Malaria Drug Resistance
Assessing Drug Resistance - in vivo
However, in the absence of molecular testing tools,
distinguishing between recrudescence and reinfection
is impossible
To overcome this limitation in areas of intense
transmission, WHO applied a modified protocol based
on clinical response rather than parasitemia
One limitation with the modified protocol is that
people with immunity will improve even if the
parasites are moderately resistant to the drug
Malaria Drug Resistance
Assessing Drug Resistance - ex vivo (in vitro)
Short-term culture of P. falciparum parasites
Blood from a parasitemic individual is prepared for
culture and incubated with increasing concentrations
of an antimalarial drug
Several assay endpoints have been developed to
measure parasite growth in the presence of different
drug concentrations
Schizont maturation
Radioisotope incorporation
Detection of parasite enzymes (LDH or HRP2)
The advantage is that these assays are independent of
individual variation in drug levels and immune
response
Malaria Drug Resistance
Assessing Drug Resistance
Genetic Polymorphisms:
There are known allelic variants that are associated
with drug resistance and are best characterized for
chloroquine and SP resistance
There are mutations that are associated with
membrane transporter proteins, decreased binding
affinity for the parasite to the drug, the encoding of
reductases.
Identification of these polymorphisms is not feasible
for case management, but their use in surveys can be
an important (but expensive) tool for monitoring drug
resistance in populations
Malaria Drug Resistance
Epidemiology of Drug resistance
Chloroquine resistance to P. falciparum was first
reported in the border areas between Venezuela
and Colombia and Thailand and Cambodia in the
1950s
Why?
Resistance didnt occur in Africa until 20 years
later, but is now widespread
In Central America and the Caribbean
chloroquine resistance has not yet been
reported
Malaria Drug Resistance

Epidemiology of Drug Resistance


In the mid-1960s, sulfadoxine-pyrimethamine
resistance was also first documented along
the Thai-Cambodian border
Why?
Resistance to SP began in Africa in the late
1980s
High level resistance most common in East
Africa
Malaria Drug Resistance

Epidemiology of Drug Resistance


Mefloquine resistance also began along the
Thai-Cambodian border, this time in the late
1980s
Why?
Clinically significant resistance to mefloquine
in Africa is rare, so it is still viable there
Malaria Drug Resistance
Epidemiology of Drug Resistance
Transmission Intensity
Low transmission: may increase rates of drug
resistance by enhancing parasite inbreeding thus
lowering the rate of genetic recombination and
increasing the probability that drug resistance
mutations would spread in the population
Inbreeding is more frequent when transmission
rates are lower since infection with multiple
different strains is less likely
Frequent emergence of resistance along the Thai-
Cambodian border supports thishowever
Malaria Drug Resistance

Zimbabwe:
Residual insecticide spraying in households to
reduce transmission
Associated with suppressed levels of drug
resistance
Therefore, the true situation must be more
complex than the simple hypothesis
Malaria - Vaccines

There is overwhelming evidence that humans


develop protective immune responses
against P. falciparum when repeatedly
exposed to infection
This suggests that the development of an
effective vaccine should be possible
Malaria - Vaccines

By 6 years of age, most children in


holoendemic areas have acquired substantial
immunity
These children are protected from severe and
fatal malaria, even though they may
demonstrate parasitemia and experience
occasional bouts of fever
However, the population pays a high price for
this immunity since the less than 5 year old
mortality from malaria is very high
Malaria - Vaccines

Vaccine development has focused on three


parasite stages:
1. Preerythrocytic sporozoite and hepatic forms
to prevent infection
2. Asexual erythrocytic forms to reduce morbidity
and mortality
3. Sexual forms within the mosquito to prevent
transmission
There are more than 90 vaccine candidates in
various stages of development, with more than
40 in clinical trials in humans
Malaria - Vaccines
Sporozoite Vaccines
Much effort has gone into sporozoite vaccines because
immunity has been induced in humans by irradiated
sporozoites
However, there is little evidence of effective natural
immunity to sporozoites
A single sporozoite that evades immune response could
potentially generate thousands of merozoites capable of
infecting red blood cells
These efforts have largely targeted the circumsporozoite
(CS) protein, an important surface component to the
parasite
Clinical trials showed that the first clinical episode and
severe malaria were reduced, but protective efficacy was
only 30% and antibody titers decayed rapidly
Malaria - Vaccines
Merozoite Vaccines
Passive immunity has been demonstrated in humans
with antimerozoite immunoglobulin
However, P. falciparum genome consists of highly
polymorphic gene families that allows successive waves
of parasites to express new variant surface antigens
Antibodies directed against these variable surface
proteins are unlikely to remain effective for long
However, there do appear to be a limited number of
conserved surface antigens against which protective
immunity can be established
The question is: how can we mimic the holoendemic
setting, that may correspond to EIRs in the hundreds,
and that induces protective immunity over many years
Malaria - Vaccines
Gametocyte Vaccines
These are aimed at blocking parasite development
within the mosquito: transmission blocking
These would not protect the vaccinated person, but
would reduce the level of transmission from those
who are infected
Preclinical studies have demonstrated that
antibodies against gametocyte antigens expressed
by P. vivax and P. falciparum can prevent the
development of infectious sporozoites in the
mosquito salivary gland
However, actual interruption of malaria transmission
in communities would require sustained high levels
of vaccine coverage
Malaria - Control

Vector Control
Breeding Site and Larva Control
Adult Vector Control
Insecticide-impregnated Treated Bed Nets
Personal and Household Protection
Malaria - Control

Treatment Strategies
Passive Case Finding and Treatment
Home Treatment
Prophylaxis
Intermittent Preventive Treatment
Malaria - Control

Vaccine Strategies
Malaria The Future

Doing better with what we have


Incorporating community-based approaches to
vector control
Incorporating community-based approaches to
home Tx and prophylaxis
Providing access to much needed affective Tx
and prophylaxis regimens
Better description and categorization of he
microepidemiology of malaria transmission
across varied geography and transmission zones