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Infectious Disease Epidemiology,[object Object],Malaria,[object Object]
Malaria,[object Object],History,[object Object],Another ancient infection: interaction and co-evolution of vertebrates, mosquitoes and Plasmodium is tens of thousands of years old,[object Object],Documentation of malaria:	,[object Object],2700 BC in China,[object Object],Homer, Plato, Aristotle, all describe malaria,[object Object],1902 Ronald Ross describes how malaria is caused by a protozoan parasite that infects the red blood cell and is transmitted by mosquito,[object Object]
Malaria,[object Object],History,[object Object],Incan civilization treatment for malaria: cinchona bark (quinine),[object Object],Jesuits bring this back to Europe in the early 17th century,[object Object],Greeks recognize the importance of low-lying water and swamps in control efforts,[object Object],Panama Canal: construction was instrumental in drainage and water environmental aspects of malarial control,[object Object],World War II,[object Object],Dichlorodiphenyltrichloroethane,[object Object],Chloroquine replaced quinine as main anti-malarial drug,[object Object]
Malaria,[object Object],Public Health Significance,[object Object],The impact of malaria varies tremendously in different parts of the world,[object Object],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,[object Object],The region most affected is the tropical belt of Africa,[object Object]
Malaria,[object Object],Public Health Significance,[object Object],Incidence and resulting disability and mortality determine any disease’s public health significance,[object Object],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,[object Object],It can be useful in areas of low to moderate transmission,[object Object],It is virtually useless in areas of high or very high transmission (holoendemicity),[object Object]
Malaria,[object Object],Public Health Significance,[object Object],1 to 2 million children die each year from malarial disease ,[object Object],~ 1 million deaths have been reported on an annual basis by WHO since the 1950s,[object Object],New Snow data,[object Object],About 90% of these deaths occur in Africa,[object Object],In Africa, malaria is one of the greatest causes of mortality in infants and children, and of disability in adults,[object Object]
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Malaria,[object Object],The Parasites and the Life Cycle,[object Object]
Malaria,[object Object],The Parasites and the Life Cycle,[object Object],Four species of protozoan parasite of the genus Plasmodium that are relevant for human infection,[object Object],P. falciparum,[object Object],P. vivax,[object Object],P. ovale,[object Object],P. malariae,[object Object],P. vivax is the most widespread malaria infection in the world,[object Object],P. falciparum causes the most severe malaria disease in the world and is responsible for the most deaths and morbidity,[object Object]
Malaria
Plasmodium Life Cycle,[object Object],The parasite undergoes several transformations with both the human host (intermediate) and mosquito host (definitive),[object Object],Transmitted to humans as sporozoites from the saliva of an infected female mosquito,[object Object],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,[object Object]
Plasmodium Life Cycle,[object Object],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,[object Object],When released from the swollen liver cells, each schizont splits into tens of thousands of daughter parasites called merozoites,[object Object],Merozoites attach to specific erythrocyte receptors and enter the erythrocyte,[object Object]
Plasmodium Life Cycle,[object Object],Each intraerythrocyticmeroziote differentiates into a trophozoite that ingests hemoglobin, enlarges, and then divides into 6 to 24 intraerythrocyticmerozoites forming a schizont,[object Object],The red cell swells and bursts, which releases the next batch of approximately 20 merozoites,[object Object],Theses new merozoites then attach and penetrate new erythrocytes to begin the cycle again,[object Object]
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Malaria
Malaria
Plasmodium Life Cycle,[object Object],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,[object Object],When synchronous, the simultaneous release from many RBCs accounts for the periodicity of these symptoms observed in many patients,[object Object],This second stage of asexual division takes 48 hours for P. falciparum, P. vivax, and P. ovale, and 72 hours for P. malariae,[object Object],A single P. falciparummerozoite can potentially lead to 10 billion new parasites through these recurrent cycles,[object Object],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,[object Object]
Plasmodium Life Cycle,[object Object],Sporogonic Development,[object Object],Once in the mosquito, the RBCs are digested, which frees the gametocytes and they then begin sexual reproduction,[object Object],The male and female gametes fuse, thus forming the zygote,[object Object],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,[object Object],During the next several days, the oocyst swells as it forms more than 10,000 sporozoites,[object Object],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,[object Object]
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Plasmodium Life Cycle,[object Object],Sporogonic Development,[object Object],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,[object Object],The time required depends on the Plasmodium species as well as temperature and humidity:,[object Object],Higher temperature and higher humidity decrease the duration of development,[object Object],Lower temperature can extend the period required (e.g. 23 days for P. falciparum at 20 degrees C),[object Object],Given the average lifespan of anophelinemosquitos is less than three weeks, temperature is critical for sporgonic (extrinsic) period of the parasite’s lifecycle,[object Object]
Plasmodium Life Cycle,[object Object],Biologic Differences Among Plasmodium Species ,[object Object],With P. vivax and P. ovale, some sporozoites entering the hepatocytes do not immediately proceed to tissue schizogony,[object Object],Those that don’t…become hypnozoites and can lie dormant for months to years,[object Object],Later these hypnozoites can differentiate and become hepatic schizonts, leading to the cycle of erythrocyticschizogony and relapse symptoms,[object Object],This biologic variant accounts for the relapses characteristic of P. vivax and P. ovale and requires specific drug treatment to target the hypnozoite stage,[object Object]
Plasmodium Life Cycle,[object Object],Biologic Differences Among Plasmodium Species,[object Object],P. falciparum does not produce hypnozoites and so does not exhibit relapse following effective treatment,[object Object],However, ineffective treatment can result in persistent low-grade parasitemia, which can lead to recrudescent clinical malaria,[object Object],Distinguish between relapse and recrudescence ,[object Object]
Plasmodium Life Cycle,[object Object],Biologic Differences Among Plasmodium Species,[object Object],Different species have different affinities for different types of erythrocytes,[object Object],P. vivax and P. ovale only invade the young reticulocytes, thus the density of peripheral parasitemia in these infections rarely exceeds 3%,[object Object],P. malariae prefers older RBCs,[object Object],P. falciparum infects erythrocytes of all ages, and so is able to produce high density parasitemias with serious morbidity and high mortality,[object Object]
Plasmodium Life Cycle,[object Object],Biologic Differences Among Plasmodium Species,[object Object],Gametocyte production varies by species,[object Object],After infection with P. vivax, gametocytes appear in the peripheral blood almost almost as soon as the asexual erythrocytic stage begins,[object Object],Gametocytes are usually present when vivax malaria is diagnosed and before antimalarialTx has begun,[object Object],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,[object Object],Therefore, drug sensitive parasites are not at a competitive disadvantage with drug resistant strains ,[object Object]
Plasmodium Life Cycle,[object Object],Biologic Differences Among Plasmodium Species,[object Object],Gametocyte production varies by species,[object Object],Following infection with P. falciparum, gametocytes appear only after several intraerythrocytic cycles, first appearing at least 10 days after the appearance of clinical disease,[object Object],Early Tx of P. falciparum with an effective drug will kill blood stage schizonts, preventing gametocytes from developing and thus blocking transmission,[object Object],However, gametocytes that do develop will be derived from parasites that survived treatment and may then carry drug resistance,[object Object],This strongly assists the selection of drug resistant parasites,[object Object],P. falciparum demonstrates much greater drug resistance than does P. vivax,[object Object]
Malaria,[object Object],AnophelineMosquitos and Their Life Cycle,[object Object],Malaria (in humans) is transmitted by mosquitoes of the genus Anopheles,[object Object],70 species are capable of transmitting human malaria, but only about 40 are important vectors,[object Object],Anopheline mosquitoes are vegetarian!,[object Object],The female anopheline requires protein derived from host blood for her egg production, thus only the female is the vector for malaria,[object Object]
Anophelines and Their Life Cycle,[object Object],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,[object Object],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),[object Object],Some are endophagic, taking blood only indoors, while others are exophagic, taking the meal outdoors,[object Object],Endophilic resting (indoors) versus exophilic resting (outdoors) after taking blood is very important in different approaches to malaria control,[object Object]
Anophelines and Their Life Cycle,[object Object],[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,[object Object],A. stephensi breeds in tin cans and confined water systems,[object Object],A. gambiae prefers small, open sunlit pools,[object Object],Understanding water preferences is also critical in approaches to vector control ,[object Object]
Anophelines and Their Life Cycle,[object Object],Four stages of growth during Anopheles life cycle,[object Object],Egg > Larva > Pupa > Adult,[object Object]
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Anophelines and Their Life Cycle,[object Object],Shortly after emerging as an adult, and before the first blood meal, adult anopheline females mate,[object Object],Typically mate once, storing sperm and laying a total of 200 to 1000 eggs in 3 to 12 batches over their adult lifetime,[object Object],A fresh blood meal is required for the development of each egg batch,[object Object],After hatching, the larva feed at the water’s surface and develop over 5 to 15 days before pupating,[object Object],The adult mosquito then emerges within 2 to 3 days,[object Object],The total cycle requires  7 to 20 days depending on the anopheline species and the environmental conditions,[object Object]
Anophelines and Their Life Cycle,[object Object],With favorable humidity and temperature, anopheline mosquitoes can survive for a month or longer,[object Object],Plenty of time to complete the 7 to 12 days sporgonic cycle ,[object Object],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,[object Object]
Anophelines and Their Life Cycle,[object Object],Anopheline mosquitoes seek out their host using a combination of chemical and physical stimuli:,[object Object],Carbon dioxide (follow the gradient),[object Object],Body odors,[object Object],Heat (follow the gradient),[object Object],Movement,[object Object],Most anophelines feed at night, but some may feed in the dusk of morning or evening,[object Object]
Anophelines and Their Life Cycle,[object Object],During feeding the mosquito injects enzymes in her saliva into the subcutaneous tissue,[object Object],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,[object Object],After feeding the engorged female must rest (24 to 36 hrs), typically on a nearby wall or secluded spot outside,[object Object],After the resting period the female then searches out a site for oviposition,[object Object]
Malaria,[object Object],Entomological Inoculation Rate (EIR),[object Object],The EIR is the number of infected bites that each person receives per night,[object Object],EIR = (HLR) X (SR),[object Object],HLR = human landing rate is the number of mosquito landings (bites) per night,[object Object],This number is obtained by capturing all mosquitoes that land on a person,[object Object],SR = ratio of infected anophelines to the total captured,[object Object],Determined by microscopic examination of dissected salivary glands to detect sporozoites,[object Object],Serologic and molecular techniques have now been developed to measure the SR,[object Object],EIR provides a direct measure of malaria transmission and the risk of human exposure to the bites of infected mosquitoes ,[object Object]
Malaria,[object Object],Vectorial Capacity,[object Object],Measures the rate of potentially infective contact, i.e. potential for malaria transmission,[object Object],Based solely on key vector parameters in a given area,[object Object],VC = ma2pn/-logp,[object Object],m is the density of vectors in relation to humans,[object Object],a is the human biting habit (proportion of blood meals taken from humans to the total number taken from any animal),[object Object],A person is bitten by ma vectors in 1 day,[object Object],p is the daily survival probability of the vector,[object Object],n is the extrinsic incubation (sporogonic) period,[object Object],pn are the vectors that survive the extrinsic cycle,[object Object],1/-logp is the daily expectation of life: each surviving vector bites a persons/day,[object Object]
Malaria,[object Object],Vectorial Capacity,[object Object],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,[object Object],In theory, the VC can predict the extent to which anopheline populations must be reduced in order to reduce transmission,[object Object],Non-linear relationship between VC and parasitemia,[object Object]
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Malaria ,[object Object],Geographic Areas by Transmission Intensity,[object Object],Holoendemic: ,[object Object],Areas of intense transmission with continuing high EIRs, where virtually everyone is infected with malaria parasites all the time,[object Object],In older children and adults, detection of parasites may be difficult because of immunity, but sufficient searching should reveal their presence,[object Object],Classification on the basis of children under age 10: spleen and parasitemia rates over 75%,[object Object]
Malaria,[object Object],Geographic Areas by Transmission Intensity,[object Object],Hyperendemic,[object Object],Areas with regular, often seasonal, transmission, but where immunity in some of the population does not confer protection at all times,[object Object],Classification on the basis of children under 10: spleen and parasitemia rates from 50% to 75%,[object Object]
Malaria,[object Object],Geographic Areas by Transmission Intensity,[object Object],Mesoendemic,[object Object],Areas that have malaria transmission fairly regularly, but at much lower levels,[object Object],The danger in these areas is occasional epidemics involving those with little immunity and resulting in fairly high morbidity and mortality,[object Object],Classification on the basis of children under 10: spleen and parasitemia rates ranging from 10% to 50%,[object Object]
Malaria,[object Object],Geographic Areas by Transmission Intensity,[object Object],Hypoendemic,[object Object],Areas with limited malaria transmission and where the population will have little or no immunity,[object Object],Classification based on children under 10: spleen and parasitemia rates less than 10%,[object Object],These areas can also have severe malaria epidemics involving all age groups,[object Object]
Malaria,[object Object],Further Classification (1990 WHO),[object Object],Eight major malaria paradigms intended to categorize typical transmission settings,[object Object],Malaria of the Africa savannah,[object Object],Forest malaria,[object Object],Malaria associated with irrigated agriculture,[object Object],Highland fringe malaria,[object Object],Desert fringe and oasis malaria,[object Object],Urban malaria,[object Object],Plains malaria,[object Object],Seashore malaria,[object Object]
Malaria - Pathogenesis,[object Object],Infection and Disease,[object Object],Infection with Plasmodium does not necessarily result in disease, especially in highly endemic areas,[object Object],In these areas, children may have parasitemia prevalence of 50% or more, and yet few will demonstrate symptoms,[object Object],However, P. falciparum malaria infection in children can range from asymptomatic to severe overwhelming disease and rapid death,[object Object],Can present with drowsiness, coma, convulsions, or simply listlessness and fever with nonspecific symptoms ,[object Object],Abdominal cramps, coughs, headaches, muscle pains, and varying levels of mental disorientation are also common,[object Object],Severe and complicated malaria due to P. falciparum is a medical emergency,[object Object]
Malaria - Pathogenesis,[object Object],Host Response,[object Object],Malaria on a population basis is the most intense stimulator of the human immune system known,[object Object],Reticuloendothelial system with enhanced phagocytosis in the spleen, lymph nodes and liver to remove infected RBCs,[object Object],Intense production of antibodies (several g/L of Ig against malaria),[object Object],A range of cell-mediated immune responses,[object Object],Cytokine cascades,[object Object],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,[object Object]
Malaria - Pathogenesis,[object Object],Host Response,[object Object],Tropical slpenomegaly,[object Object],Fairly common among relatively nonimmune populations (become exposed because they move, or because of a change in climate),[object Object],Begins in childhood and progresses through adolescence to young adulthood with:,[object Object],Severe anemia,[object Object],High levels of IgM and anti-malaria antibodies,[object Object],Decrease in platelets,[object Object],Enlarged spleen,[object Object],Parasites are rarely detectable,[object Object],If untreated it is often fatal, usually due to secondary infection,[object Object]
Malaria - Pathogenesis,[object Object],Host Response,[object Object],Plasmodium parasites have evolved many complex mechanisms to evade the host immune response and establish persistent or repeated infection,[object Object],As such, protective immunity following natural infection takes many years to develop,[object Object],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,[object Object]
Malaria - Pathogenesis,[object Object],Host Response,[object Object],Antibodies to the circumsporozoite protein can prevent the sporozoites from binding to liver cells,[object Object],Cellular immune responses, in particular interferon gamma producing T cells, are important in killing infected liver cells,[object Object],Both humoral and cell-mediated immunity play roles in killing parasitized RBCs,[object Object],Antibodies to erythrocytic stages may act through monocytes in a process called antibody-dependent cellular inhibition,[object Object]
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Malaria - Pathogenesis,[object Object],Undernutrition and Micronutrient Deficiencies,[object Object],Malaria is prevalent in areas where childhood malnutrition is common,[object Object],Nutritional deficiencies interact with malaria infection ,[object Object]
Malaria - Pathogenesis,[object Object],Undernutrition and Micronutrient Deficiencies,[object Object],Protein-energy malnutrition (PEM): a group of related disorders that include marasmus, kwashiorkor, and intermediate stages,[object Object],Marasmus: ,[object Object],Inadequate intake of protein and calories ,[object Object],Deficient in all nutrients ,[object Object],Essentially starvation,[object Object],Characterized by emaciation,[object Object],Kwashiorkor: ,[object Object],Inadequate protein intake, but with reasonable caloric (carbohydrates) intake,[object Object],Characterized by edema,[object Object]
Malaria - Pathogenesis,[object Object],Undernutrition and Micronutrient Deficiencies,[object Object],All forms of PEM impair the functioning of all body systems and particularly cellular and humoral immunity,[object Object],Recent evidence demonstrates that malnourished children are more likely to die from malaria than adequately nourished children,[object Object],Malaria prophylaxis should be provided to malnourished children in malaria areas when treating PEM,[object Object]
Malaria - Pathogenesis,[object Object],Undernutrition and Micronutrient Deficiencies,[object Object],Iron deficiency is the most common micronutrient deficiency and is associated with defects in the immune response and poor health outcomes,[object Object],However, iron supplementation may increase the level of parasitemia (significant) and clinical attack rates (not significant),[object Object],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,[object Object]
Malaria - Pathogenesis,[object Object],Undernutrition and Micronutrient Deficiencies,[object Object],Vitamin A is essential for proper immune function,[object Object],Supplementation can reduce clinical attack rates (number of clinical episodes), splenic enlargement, and parasetemia,[object Object],Most relevant for young children,[object Object],Fraction of malaria morbidity attributable to Vitamin A deficiency may be as high as 20% worldwide,[object Object],These are based on very limited data,[object Object]
Malaria - Pathogenesis,[object Object],Undernutrition and Micronutrient Deficiencies,[object Object],Zinc is also essential for proper immune function, both humoral and cell-mediated,[object Object],Zinc supplementation reduces clinical attack rates, especially attacks with high density parasitemia,[object Object],Fraction of malaria morbidity attributable to zinc deficiency may also be as high as 20% worldwide,[object Object]
Falciparum Malaria Disease,[object Object],Severe Malaria,[object Object],Disease caused by P. falciparum is a major cause of death in children wherever there is a high intensity of infection,[object Object],Malaria may account for half the mortality rate for children under 5 years old in holoendemic areas,[object Object],In holoendemic areas severe disease in children does not progress from mild or moderate illness…it strikes abruptly without warning,[object Object],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),[object Object],Rapid progression to severe disease is not characteristic in areas with less intense transmission,[object Object]
Falciparum Malaria Disease,[object Object],Severe Malaria,[object Object],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: ,[object Object],Cerebral malaria (median time of 5 days from onset to cerebral symptoms) and multiple organ dysfunction syndrome (MODS) (median time of 8 days),[object Object],Early effective Tx before the onset of the severe phase is the key to reducing mortality,[object Object],The slow progressing form is much less common in holoendemic areas and therefore less common in much of Africa,[object Object]
Falciparum Malaria Disease,[object Object],Clinical Patterns,[object Object],WHO Criteria for severe malaria 1990,[object Object],Coma,[object Object],Severe anemia,[object Object],Respiratory distress,[object Object],Hypoglycemia,[object Object],Circulatory collapse,[object Object],Renal failure,[object Object],Spontaneous bleeding,[object Object],Repeated convulsions,[object Object],Acidosis,[object Object],Hemoglobinuria,[object Object],Addition WHO criteria for severe malaria 2000,[object Object],Impaired consciousness,[object Object],Prostration,[object Object],Hyperparasitemia,[object Object],Hyperpyrexia,[object Object],Hyperbilirubinemia,[object Object]
Falciparum Malaria Disease,[object Object],Clinical Patterns,[object Object],Most children presenting with severe malaria can be placed in 1 of 3 distinctive syndromes:,[object Object],2 syndromes that are readily delineated clinically when the child is first seen:,[object Object],Neurologic deficit – about 20% of hospital admissions with about 15% case fatality,[object Object],Respiratory distress – about 14% of admissions also with about 15% case fatality,[object Object],The third, also life-threatening syndrome, is not so readily apparent clinically,[object Object],Severe anemia – about 18% of admissions with about 5% mortality ,[object Object]
Falciparum Malaria Disease,[object Object],Clinical Patterns,[object Object],Hypoglycemia and metabolic acidosis are central in the pathogenesis of severe malaria,[object Object],Hypoglycemia has been estimated at about 14% prevalent (similar to respiratory distress) with 22% case fatality,[object Object]
Malaria
Falciparum Malaria Disease,[object Object],Cerebral Malaria,[object Object],Histopathologically due to the massive sequestration of infected cells in the cerebral microvasculature,[object Object],Case-fatality ranges from 10% to 50%,[object Object],CM is heterogeneous with 4 overlapping syndromes with different pathogenic mechanisms,[object Object],Prolonged postictal state, characterized as deep sleep, headache, confusion and muscle soreness,[object Object],Covert status epilepticus, characterized by continual seizures,[object Object],Severe metabolic derangement, particularly with hypoglycemia and metabolic acidosis,[object Object],Commonly more than 1 coexist, and recognition and management of all, plus malaria Tx, must be implemented,[object Object]
Falciparum Malaria Disease,[object Object],Respiratory Distress,[object Object],Pulmonary edema, often seen with acute respiratory distress syndrome has long been recognized as  a serious, often fatal, complication of malaria,[object Object],Respiratory distress is a valuable defining characteristic because the clinical signs can be applied with good interobserver consistency, and with minimal training,[object Object],The clinical signs of hyperventilation (driven by efforts to reduce CO2) are highly sensitive and specific for the diagnosis of respiratory distress ,[object Object]
Falciparum Malaria Disease,[object Object],Respiratory Distress,[object Object],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,[object Object],Main factor is metabolic acidosis largely due to lactate production caused by reduced oxygen to the tissues,[object Object]
Falciparum Malaria Disease,[object Object],Severe Anemia,[object Object],Complex pathogenesis  and varies greatly geographically because of its interaction with PEM and iron deficiency,[object Object],Tends to be the predominant form of severe malaria in areas of the most intense transmission and is common in the youngest age groups,[object Object],Malnutrition, anemia and dehydration influence the Tx and expected outcomes of severe malaria,[object Object],Malnourished children are at increased risk of death from malaria,[object Object]
Falciparum Malaria Disease,[object Object],Epidemiologic Features of Severe Malaria,[object Object],As the intensity of transmission increases, the proportion of the population with severe malaria shifts to the younger age groups,[object Object],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,[object Object]
Falciparum Malaria Disease,[object Object],Epidemiologic Features of Severe Malaria,[object Object],In endemic areas, the pattern of severe morbidity varies with age,[object Object],Severe anemia predominates in younger children (median age 15 to 24 months),[object Object],Coma is more common in older children (median age 36 to 48 months),[object Object]
Falciparum Malaria Disease,[object Object],Epidemiologic Features of Severe Malaria,[object Object],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,[object Object],For example,[object Object],EIR = 100 bites/year:  severe malaria presents more commonly as severe anemia at younger ages,[object Object],EIR = 10 bites/year: severe malaria presents more commonly as cerebral symptoms at an older age,[object Object],Also, constancy of transmission is important:,[object Object],Intense perennial transmission is associated with severe anemia in severe malaria ,[object Object],Intense seasonal transmission is associated with cerebral malaria in severe malaria,[object Object]
Falciparum Malaria Disease,[object Object],Epidemiologic Features of Severe Malaria,[object Object],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,[object Object],When malaria is controlled in holoendemic areas, a major reduction in overall child mortality follows,[object Object]
Falciparum Malaria Disease,[object Object],Malaria in Pregnancy,[object Object],Women infected with malaria while pregnant are at much greater risk of serious disease and complications than women who are not pregnant or men,[object Object],Host defense mechanisms to malaria are greatly diminished during pregnancy and for several weeks postpartum with reductions in both cell-mediated and humoral responses,[object Object]
Falciparum Malaria Disease,[object Object],Malaria in Pregnancy ,[object Object],In all areas endemic for malaria, pregnant women are more likely to be bitten by malaria vectors,[object Object],Higher metabolic rate in pregnancy:,[object Object],Increases body temperature,[object Object],Increases CO2 release,[object Object],Can also be behavioral,[object Object],E.g., pregnant women who have to leave home in the night more frequently to urinate,[object Object],Pregnant women are at higher risk of infection with all Plasmodium species, and are at increased risk for all malaria types,[object Object],At higher risk for severe, complicated malaria and death,[object Object]
Falciparum Malaria Disease,[object Object],Malaria in Pregnancy,[object Object],The maternal mortality rate ranges from 100 to over 1000 per 100,000 live births,[object Object],This MMR is the same in low and high transmission areas,[object Object],However, the nature of the complications is different, as are those at risk (e.g. first pregnancies),[object Object]
Falciparum Malaria Disease,[object Object],Malaria in Pregnancy,[object Object],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,[object Object],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 ,[object Object]
Falciparum Malaria Disease,[object Object],Malaria in Pregnancy,[object Object],Adverse outcomes of the pregnancies are higher in women with malaria because of active malaria infection of the placenta,[object Object],Effects of both past and present placental infections combined with the often-intense host responses contribute to the high fetal losses associated with malaria,[object Object],First pregnancy versus subsequent,[object Object],Uterine immunology is naïve relative to the mother’s otherwise systemic immune responses,[object Object]
Falciparum Malaria Disease,[object Object],Malaria in Pregnancy,[object Object],Higher rates of low weight births and still births,[object Object],Low birth weight is increased in both low and high transmission areas, but for different reasons:,[object Object],Low transmission areas have more pre-term delivery,[object Object],High transmission areas have more fetal growth retardation,[object Object],Higher rates of perinatal and infant mortality (follows from the above),[object Object]
Falciparum Malaria Disease,[object Object],Malaria in Pregnancy,[object Object],Population Attributable Risk:,[object Object],Low birth weight: 8% to 14%,[object Object],Pre-term delivery: 8% to 36%,[object Object],Fetal growth retardation: 13% to 70%,[object Object],Infant mortality: 3% to 8%,[object Object]
Falciparum Malaria Disease,[object Object],Malaria in Pregnancy,[object Object],The greatest risk is associated with malaria infection is in the second and third trimester,[object Object],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),[object Object]
Malaria – Human Activities and Epidemiology,[object Object],Agricultural development, population movement, and urbanization are important determinants of the pattern of malaria transmission,[object Object]
Malaria – Human Activities and Epidemiology,[object Object],Agriculture,[object Object],Malaria has long been linked to farming practices ,[object Object],In sub-Saharan African, the clearing of forest for crop production has lead to increased breeding Anopheles gambiae,[object Object],The most efficient vector of human malaria,[object Object],Prefers sunlit open pools of standing water to the full shade of tropical forest,[object Object],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,[object Object],Agricultural use of pesticides has led to insecticide-resistant vectors,[object Object]
Malaria – Human Activities and Epidemiology,[object Object],Population movement,[object Object],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,[object Object],Often the intensity of transmission is much higher in these areas than in their settled villages where water supplies are controlled,[object Object],Also, many pastoral people are exposed to areas of high transmission as they move their livestock from highland to lowland pastures with the seasons,[object Object]
Malaria – Human Activities and Epidemiology,[object Object],Population Movement,[object Object],Drought, famine and conflict lead to massive population displacement and refugee movements,[object Object],Movements often from more settled areas to fringe areas,[object Object],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,[object Object],All of these contribute to increased malaria transmission,[object Object]
Malaria – Human Activities and Epidemiology,[object Object],Population Movement,[object Object],The majority of modern migration is to urban areas,[object Object],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 ,[object Object],However, some anopheline species have become well adapted to the urban environment (A. arabensis),[object Object],Urban anophelines are typically restricted to semi-urban slum areas, rather than concentrated city centers,[object Object]
Malaria – Human Activities and Epidemiology,[object Object],Socioeconomic Status,[object Object],Malaria can strike in anyone, but it is principally a disease of the poor,[object Object],Loss of healthy life due to malaria is much higher in poor rural areas,[object Object],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,[object Object]
Malaria – Human Activities and Epidemiology,[object Object],Health Seeking Behavior,[object Object],Importance of cultural practice and beliefs,[object Object],Importance of misunderstanding the symptoms of cerebral malaria because of convulsions and confusion,[object Object]
Malaria – Diagnosis and Treatment,[object Object],A definitive diagnosis is made by demonstration of parasites in red blood cells,[object Object],Gold standard technique is microscopic examination of Giemsa-stained thick and thin smears of blood (thick smear is more sensitive),[object Object]
Malaria – Diagnosis and Treatment,[object Object],Problems with Blood Smears - Implementation,[object Object],Work is very tedious and requires continuous concentration,[object Object],Delays in viewing smears result in delays in Tx,[object Object],Maintenance of the microscope and staining materials requires rigorous control,[object Object],Training technicians and monitoring their work requires sustained effort,[object Object]
Malaria – Diagnosis and Treatment,[object Object],Problems with blood smears – Interpretation,[object Object],Peripheral smears may be falsely negative before RBCs are infected and later during schizogony when infected RBCs are sequestered in the capillary beds,[object Object],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,[object Object],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,[object Object]
Malaria – Diagnosis and Treatment,[object Object],Treatment – History,[object Object],Cinchona bark used by Incas and Peruvians for thousands of years,[object Object],This was brought back to Europe in the 17th century by Jesuit missionaries,[object Object],In 1820 the active ingredient was identified as the alkaloid quinine (still an effective agent against drug-resistant falciparum malaria),[object Object],Chloroquine was synthesized in the late 1930s in Germany. During World War II it was captured and recognized to be highly effective against malaria,[object Object]
Malaria – Diagnosis and Treatment,[object Object],Treatment – Chloroquine,[object Object],Rapidly absorbed after oral administration,[object Object],Active against the asexual stages of all human species except for strains of P. falciparum that have become resistant ,[object Object],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,[object Object],In appropriate doses, chloroquine is well tolerated even when taken for long periods and is safe for young children and pregnant women,[object Object],Because of low toxicity, low cost, and effectiveness this was the malaria drug of choice for decades following World War II ,[object Object]
Malaria – Diagnosis and Treatment,[object Object],Treatment – Primaquine,[object Object],Developed by the US Army during World War II,[object Object],The only drug effective against sporozoites and the hepatic forms:,[object Object],Thus, it can be used to prevent infection in the liver (known as “causal prophylaxis”),[object Object],It can also be used to eliminate the hypnozoite stage of P. vivax and P. ovale (anti-relapse treatment),[object Object],The drug is also effective in eliminating gametocytes:,[object Object],Theoretically it could play a role in reducing transmission and preventing the spread of drug resistant strains,[object Object],However, primaquine does cause hemolysis in people with glucose-6-phosphate dehydrogenase deficiency, which is common in those of Mediterranean and African descent,[object Object]
Malaria – Diagnosis and Treatment,[object Object],Treatment – Sulfadoxine-pyrimethamine,[object Object],Originally developed for it’s efficacy against chloroquine-resitant P. falciparum,[object Object],Has been widely used to replace chloroquine in areas of drug resistance,[object Object],Because it is single-dose therapy and inexpensive, SP is widely used in Africa to treat malaria,[object Object],This is the preferred antimalarial for pregnant women,[object Object],Can be used for intermittent prophylactic treatment of young children,[object Object],There can be some adverse reactions (Stevens-Johnson syndrome) when used for prophylaxis ,[object Object]
Malaria – Diagnosis and Treatment,[object Object],Treatment,[object Object],Chloroquine and SP have been the most commonly used drugs to treat malaria in Africa, but widespread drug resistance has significantly reduced their effectiveness,[object Object]
Malaria – Diagnosis and Treatment,[object Object],Treatment – Mefloquine,[object Object],Developed in the late 1960s by the US Army for its activity against chloroquine resistant P. falciparum,[object Object],Used for prophylaxis and for treatment in combination with artesunate in Southeast Asia,[object Object],Resistance to mefloquine has now emerged in Southeast Asia,[object Object],Frequent reports of adverse mental reactions have led to reduction in its use in general ,[object Object]
Malaria – Diagnosis and Treatment,[object Object],Treatment – Artemisinin (and related compounds – artesunate, arthemether),[object Object],The active agent of the Chinese herbal medicine (Artemisia annua),[object Object],Inhibits the P. falciparum ATP6, a calcium-pumping enzyme,[object Object],The drugs quickly clear blood stage parasites and gametocytes,[object Object],Provide a rapid clinical response,[object Object],Resistance to artemisinins has not been observed yet,[object Object],However, when used alone, recrudescence is common so these are usually combined with other antimalarials,[object Object]
Malaria – Drug Resistance,[object Object],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,[object Object],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,[object Object],Resistance to more recently introduced antimalarials, like mefloquine, developed very fast,[object Object],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,[object Object],Drug resistance is largely associated with P. falciparum (though some chloroquine resistant P.vivax exists in PNG).,[object Object]
Malaria – Drug Resistance,[object Object],Contributing factors,[object Object],Pharmacologic properties of the drug:,[object Object],Prolonged half-life,[object Object],Poor compliance,[object Object],Inappropriate use,[object Object],All these can cause the parasites to receive subtherapeutic drug levels,[object Object],Host immunity:,[object Object],Relevance of immunologically naïve hosts,[object Object],Parasite genetics – antigenic variation,[object Object],Transmission characteristics:,[object Object],Level of endemicity,[object Object],Species of mosquito and its behavior,[object Object]
Malaria – Drug Resistance,[object Object],Assessing Drug Resistance,[object Object],Evaluation of therapeutic responses in vivo,[object Object],Measurement of parasite growth ex vivo,[object Object],Identification of genetic mutations associated with resistance,[object Object]
Malaria – Drug Resistance,[object Object],Assessing Drug Resistance – in vivo,[object Object],Traditional in vivo testing developed by WHO,[object Object],Infected patients are given an antimalarial drug according to an established regime,[object Object],Parasite counts are made at the start of therapy, at 24 hours, at 7 days and at 28 days after the start of Tx,[object Object],If parasites are not detected at the end of 7 days (and still not at 28 days) the parasites are considered sensitive,[object Object],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,[object Object],If there is reduction in parasitemia but not complete clearance at 7 days, the parasites are considered stage RII resistant,[object Object],If there is no evidence of response, the parasites are considered fully resistant, stage RIII,[object Object]
Malaria – Drug Resistance,[object Object],Assessing Drug Resistance -  in vivo,[object Object],However, in the absence of molecular testing tools, distinguishing between recrudescence and reinfection is impossible,[object Object],To overcome this limitation in areas of intense transmission, WHO applied a modified protocol based on clinical response rather than parasitemia,[object Object],One limitation with the modified protocol is that people with immunity will improve even if the parasites are moderately resistant to the drug,[object Object]
Malaria – Drug Resistance,[object Object],Assessing Drug Resistance - ex vivo (in vitro),[object Object],Short-term culture of P. falciparum parasites,[object Object],Blood from a parasitemic individual is prepared for culture and incubated with increasing concentrations of an antimalarial drug,[object Object],Several assay endpoints have been developed to measure parasite growth in the presence of different drug concentrations,[object Object],Schizont maturation,[object Object],Radioisotope incorporation,[object Object],Detection of parasite enzymes (LDH or HRP2),[object Object],The advantage is that these assays are independent of individual variation in drug levels and immune response,[object Object]
Malaria – Drug Resistance,[object Object],Assessing Drug Resistance,[object Object],Genetic Polymorphisms:,[object Object],There are known allelic variants that are associated with drug resistance and are best characterized for chloroquine and SP resistance,[object Object],There are mutations that are associated with membrane transporter proteins, decreased binding affinity for the parasite to the drug, the encoding of reductases.,[object Object],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 ,[object Object]
Malaria – Drug Resistance,[object Object],Epidemiology of Drug resistance,[object Object],Chloroquine resistance to P. falciparum was first reported in the border areas between Venezuela and Colombia and Thailand and Cambodia in the 1950s,[object Object],Why?,[object Object],Resistance didn’t occur in Africa until 20 years later, but is now widespread,[object Object],In Central America and the Caribbean chloroquine resistance has not yet been reported,[object Object]
Malaria – Drug Resistance,[object Object],Epidemiology of Drug Resistance,[object Object],In the mid-1960s, sulfadoxine-pyrimethamine resistance was also first documented along the Thai-Cambodian border,[object Object],Why?,[object Object],Resistance to SP began in Africa in the late 1980s,[object Object],High level resistance most common in East Africa,[object Object]
Malaria – Drug Resistance,[object Object],Epidemiology of Drug Resistance,[object Object],Mefloquine resistance also began along the Thai-Cambodian border, this time in the late 1980s,[object Object],Why?,[object Object],Clinically significant resistance to mefloquine in Africa is rare, so it is still viable there,[object Object]
Malaria – Drug Resistance,[object Object],Epidemiology of Drug Resistance,[object Object],Transmission Intensity,[object Object],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,[object Object],Inbreeding is more frequent when transmission rates are lower since infection with multiple different strains is less likely,[object Object],Frequent emergence of resistance along the Thai-Cambodian border supports this…however…,[object Object]
Malaria – Drug Resistance,[object Object],…Zimbabwe:,[object Object],Residual insecticide spraying in households to reduce transmission,[object Object],Associated with suppressed levels of drug resistance,[object Object],Therefore, the true situation must be more complex than the simple hypothesis,[object Object]
Malaria - Vaccines,[object Object],There is overwhelming evidence that humans develop protective immune responses against P. falciparum when repeatedly exposed to infection,[object Object],This suggests that the development of an effective vaccine should be possible,[object Object]
Malaria - Vaccines,[object Object],By 6 years of age, most children in holoendemic areas have acquired substantial immunity,[object Object],These children are protected from severe and fatal malaria, even though they may demonstrate parasitemia and experience occasional bouts of fever,[object Object],However, the population pays a high price for this immunity since the less than 5 year old mortality from malaria is very high,[object Object]
Malaria - Vaccines,[object Object],Vaccine development has focused on three parasite stages:,[object Object],Preerythrocyticsporozoite and hepatic forms to prevent infection,[object Object],Asexual erythrocytic forms to reduce morbidity and mortality,[object Object],Sexual forms within the mosquito to prevent transmission,[object Object],There are more than 90 vaccine candidates in various stages of development, with more than 40 in clinical trials in humans,[object Object]
Malaria - Vaccines,[object Object],Sporozoite Vaccines,[object Object],Much effort has gone into sporozoite vaccines because immunity has been induced in humans by irradiated sporozoites,[object Object],However, there is little evidence of effective natural immunity to sporozoites,[object Object],A single sporozoite that evades immune response could potentially generate thousands of merozoites capable of infecting red blood cells,[object Object],These efforts have largely targeted the circumsporozoite (CS) protein, an important surface component to the parasite,[object Object],Clinical trials showed that the first clinical episode and severe malaria were reduced, but protective efficacy was only 30% and antibody titers decayed rapidly,[object Object]
Malaria - Vaccines,[object Object],Merozoite Vaccines,[object Object],Passive immunity has been demonstrated in humans with antimerozoite immunoglobulin,[object Object],However, P. falciparum genome consists of highly polymorphic gene families that allows successive waves of parasites to express new variant surface antigens,[object Object],Antibodies directed against these variable surface proteins are unlikely to remain effective for long,[object Object],However, there do appear to be a limited number of conserved surface antigens against which protective immunity can be established,[object Object],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,[object Object]
Malaria - Vaccines,[object Object],Gametocyte Vaccines,[object Object],These are aimed at blocking parasite development within the mosquito: “transmission blocking”,[object Object],These would not protect the vaccinated person, but would reduce the level of transmission from those who are infected,[object Object],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,[object Object],However, actual interruption of malaria transmission in communities would require sustained high levels of vaccine coverage,[object Object]
Malaria - Control,[object Object],Vector Control,[object Object],Breeding Site and Larva Control,[object Object],Adult Vector Control,[object Object],Insecticide-impregnated Treated Bed Nets,[object Object],Personal and Household Protection,[object Object]
Malaria - Control,[object Object],Treatment Strategies,[object Object],Passive Case Finding and Treatment,[object Object],Home Treatment,[object Object],Prophylaxis,[object Object],Intermittent Preventive Treatment,[object Object]
Malaria - Control,[object Object],Vaccine Strategies,[object Object]
Malaria – The Future,[object Object],Doing better with what we have,[object Object],Incorporating community-based approaches to vector control,[object Object],Incorporating community-based approaches to home Tx and prophylaxis,[object Object],Providing access to much needed affective Tx and prophylaxis regimens,[object Object],Better description and categorization of he microepidemiology of malaria transmission across varied geography and transmission zones,[object Object]

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