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My lecture on malaria
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INFECTIOUS DISEASE EPIDEMIOLOGY
Malaria
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) Jesuits bring this back to Europe in the early 17th century
Greeks recognize the importance of low-lying water and swamps in control efforts
Panama Canal: construction was instrumental in drainage and water environmental aspects of malarial control
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 disease’s 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 New Snow data 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 host’s repsonse to these toxins correspond with the clinical paroxysms of fever and chills
When synchronous, 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 mosquito’s stomach where it will become and 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 sporgonic (extrinsic) period of the parasite’s 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 don’t…become 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 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 it’s 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 water’s 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 sporgonic 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 mosquito’s 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 illness…it 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 naïve relative to the
mother’s 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 it’s 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 naïve 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 didn’t 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 this…however…
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