Malaria

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 intraerythrocyticmeroziote differentiates into a trophozoite that ingests hemoglobin, enlarges, and then divides into 6 to 24 intraerythrocyticmerozoites 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. falciparummerozoite 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 anophelinemosquitos 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 erythrocyticschizogony 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 antimalarialTx 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 AnophelineMosquitos 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 ,[object Object],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: Preerythrocyticsporozoite and hepatic forms to prevent infection Asexual erythrocytic forms to reduce morbidity and mortality 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

Malaria

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