Malaria

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By: kylai23 (57 month(s) ago)

This powerpoint is prepared in support of the World Malaria Day on 25 April 2010 and to celebrate the success of the ROLL BACK MALARIA programo f W.H.O.. It also emphasizes how traditional chinese medicine and our modern understanding of the important role of apicoplast and food vacuoles in the life cycle of the malaria parasite have help us finding out effective anti-malarial drug in the treatment of drug-resistant plasmodium falciparum.

Presentation Transcript

Malaria 2010 : 

Malaria 2010 Dr. Lai Kang Yiu Intensive Care Unit Queen Elizabeth Hospital There is a Plant inside Malaria ! (secondary endosymbiosis) Malaria -Plasmodium- contains a broken down old chloroplast (an Apicoplast) that doesn't do any photosynthesizing The Apicoplast is however, needed for the parasite to invade new cells. Even more fascinating- common herbicides that are generally pretty non-toxic to humans seem to stop the Apicoplast from working. Plasmodium falciparum O =Apicoplast

Malaria : 

Malaria 1, first inner membrane; 2, second inner membrane; 3, periplastid membrane; 4, outer membrane; L, lumen; P, periplastid space; E, exoplastid space; CS, contact site. Malaria (Apicoplast)

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Apicoplast (the green dots inside the round malaria parasites) is responsible for metabolic pathways for type II fatty acid synthesis, non-mevalonate isoprenoid synthesis and a portion of heme synthesis. It contains an independent genome, encoding prokaryotelike RNA polymerase subunits, 70S ribosomal subunits, tRNAs, and a small number of proteins Foth, B.J. et al. Dissecting apicoplast targeting in the malaria parasite Plasmodium falciparum. Science 299, 705-708 (January 31, 2003).  Missinou, M.A. et al. Fosmidomycin for Malaria. The Lancet 360, 1941-1942.Jomaa, H. et al. Inhibitors of the Nonmevalonate Pathway of Isoprenoid Biosynthesis as Antimalarial Drugs. Science 285, 1573-1576. Blue- food vacuoles Orange-nuclei Red-apicoplast Malaria inside RBC Fosmidomycin is an antibiotic that specifically inhibits DXP reductoisomerase, a key enzyme in the non-mevalonate pathway and is synergistic with clindamycin against malaria.

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Nature 419, 498-511 (3 October 2002)

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Block expression of the apicoplast genome, resulting in the distribution of nonfunctional apicoplasts into daughter merozoites leading to delayed cell death Rifampin killed parasites quickly, preventing them from initiating cell division. Multiple Antibiotics Exert Delayed Effects against the Plasmodium falciparum Apicoplast_ Erica L. Dahl and Philip J. Rosenthal ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Oct. 2007, p. 3485–3490 The apicoplast houses enzymes involved in type II fatty acid synthesis, a nonmevalonate pathway for isoprenoid biosynthesis, and heme-biosynthetic pathways

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90% cases 72 species of anopheles mosquito (♀) Malaria is the most common life-threatening infection 1 million deaths/yr 300-500 million infections/yr 1 child dies of malaria every 30 seconds ~90% of these deaths occur in sub-Saharan Africa Most victims are children <5 yrs due to immunity built up in older population (Older people are susceptible when they move from one area and return outside of 6 months Pregnant women are also especially vulnerable. Factors favoring spread: At low altitudes During hot seasons In places where the Anopheles mosquito is able to breed in fresh water

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2700 B.C. in China, Huang Di Nei Jing has described 瘧 (Nüe) as one form of intermittent fever recurring every one. two or three days. Effective treatment of malaria usuing Qinghao (青蒿 from Artemisia annua) was introduced in China by Ge Hong in Jìn Dynasty. Ge Hong 284–363肘後備急方 黃帝內經素問第十卷內有《瘧論篇》和《刺論篇》等專篇論述瘧疾的病因、症狀和療法,並從發作規律上分為“日作”、“間日作” 與 “三日作”。

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Hippocratic corpus (400 B.C.) distinguished the intermittent malarial fever from the continuous fever of other infectious diseases, and also noted the daily, every-other-day, and every-third-day temperature rise and described the splenomegaly of malaria.

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Alexander the Great is believed to have died of malaria in 323 BC, on the route to India beyond Mesopotamia

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Matthew (8:14-15) ‘‘Peter’s mother-in-law was lying sick of a fever’’ Malaria is common around the swampy ground around the Lake of Galilee.

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Genghis Khan, the Mongol overlord of the 13th Century who set up the largest land empire ever known, is believed to have suffered from a malaria like illness in the spring of 1227, even as he was nursing his injuries. After several months of sickness, the Great Khan died at age 60.

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Oliver Cromwell, Lord Protector, England's first and only dictator died of malaria in 1658 King Charles I, (1600-1649) was beheaded on 30/1/1649

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William Shakespeare (1564–1616 mentioned ague (malaria) in eight of his plays. Malaria was an important cause of illness and death in several parts of England. From Shakespeare to Defoe: Malaria in England in the Little Ice Age Paul Reiter Centers for Disease Control and Prevention, San Juan, Puerto Rico King John, Constance–lamenting the fate of her son–says But now will canker-sorrow eat my bud   And chase the native beauty from his cheek   And he will look as hollow as a ghost,    As dim and meagre as an ague's fit.”

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Green- No known malaria risk Yellow – Varied malaria risk Red – Malaria risk throughout country Malaria Worldwide

The global distribution of malaria since preintervention (˜1900–2002)[Hay SI, Guerra CA, Tatem AJ, et al. The global distribution and population at risk of malaria: past, present, and future. Lancet Infect Dis 2004;4 (6):327–36.] : 

The global distribution of malaria since preintervention (˜1900–2002)[Hay SI, Guerra CA, Tatem AJ, et al. The global distribution and population at risk of malaria: past, present, and future. Lancet Infect Dis 2004;4 (6):327–36.] The Contraction of Malarial Zone due to Human Intervention

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At present, 45 percent of the world has conditions that permit malaria transmission. The Intergovernmental Panel on Climate Change estimates that warming of 3° to 5°C could expand the zone of potential transmission to include 60 percent of the globe.

MAJOR VECTORBORNE TROPICAL DISEASESImpact of Global Warming : 

MAJOR VECTORBORNE TROPICAL DISEASESImpact of Global Warming

Among diseases that mosquitoes spread are West Nile virus, malaria, yellow fever, dengue fever, and Arboviral Encephalitides such as Eastern and Western equine encephalitis, St. Louis encephalitis, and La Crosse fever. : 

Among diseases that mosquitoes spread are West Nile virus, malaria, yellow fever, dengue fever, and Arboviral Encephalitides such as Eastern and Western equine encephalitis, St. Louis encephalitis, and La Crosse fever. Aedes aegypti West Nile virus Tropical and temperate regions Birds humans, horses, and some other mammals yellow fever Aedes japonicus Aedes albopictus Culex pipiens T > 81° F (27°C) Bird  human transmission in U.S.A. Culex restuans infects primarily birds, but not people, and is dominant in the spring and early summer Culex restuans Culex restuans Culex pipiens

Diseases Due to Global Warming : 

Diseases Due to Global Warming Copepod 繞足動物 Assassin bugs (or kissing bugs) sand flies tsetse fly Sleeping sickness Chagas Disease Leishmaniasis

Filariasis : 

Filariasis Deer fly

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The Life Cycle of Malaria

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Red Blood Cell Invasion : Plasmodium falciparum

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Plasmodium falciparum parasitizes red blood cells (RBCs) and resides in a specialized vacuole formed during host-cell invasion. A new study3 suggests that the parasite installs a protein complex (PTEX) in the vacuole membrane that enables it to export hundreds of parasite proteins into the RBC cytoplasm. Maurer's clefts and knobs are structures found only in infected RBCs, and their formation and function probably depend on the activity of the exported parasite proteins.

Malaria-carrying female Anopheles mosquito tend to bite only between dusk and dawn.(Image courtesy of James Gathany and the Centers for Disease Control and Prevention) : 

Malaria-carrying female Anopheles mosquito tend to bite only between dusk and dawn.(Image courtesy of James Gathany and the Centers for Disease Control and Prevention)

Sickle Cell Trait and Malaria : 

Sickle Cell Trait and Malaria People with sickle cell disease can get malaria just like anyone else. However, people with sickle cell trait are less likely to get malaria. The trait doesn't completely protect a person from infection, but it makes death from malaria less likely.

Theories as to why people with sickle cell trait have milder cases of malaria : 

Theories as to why people with sickle cell trait have milder cases of malaria The parasite inside the red cell produces acid. In the presence of acid, HbS has a tendency to polymerize which causes the cells to sickle. Since sickled cells are destroyed as the blood circulates through the spleen, the parasites are destroyed as well. Malarial parasites do not live long under low oxygen conditions. Since the oxygen concentration is low in the spleen, and since infected red cells tend to get trapped in the spleen, they may be killed there. Another thing that happens under low oxygen conditions is that potassium leaks out of HbS-containing cells. The parasite needs high potassium levels to develop. This may be the reason the parasite fails to thrive in red blood containing Hb S.

Thalassaemia Trait and MalariaWillcox M, Bjorkman A, Brohult J. Falciparum malaria and beta-thalassaemia trait in northern Liberia. Ann Trop Med Parasitol. 1983;77:335–347 : 

Thalassaemia Trait and MalariaWillcox M, Bjorkman A, Brohult J. Falciparum malaria and beta-thalassaemia trait in northern Liberia. Ann Trop Med Parasitol. 1983;77:335–347 Carrier of thalassaemia trait make the red blood cells more susceptible to the less lethal species Plasmodium vivax, simultaneously making the host RBC environment unsuitable for the merozoites of the lethal strain Plasmodium falciparum. This is believed to be a selective survival advantage for patients with the various thalassemia traits. ß-thalassaemia heterozygotes one-to-four years old appear to have a relative risk of 0.45 for contacting malaria (Willcox 1983)

Α-Thalassaemia and MalariaWambua S, Mwangi TW, Kortok M, Uyoga SM, Macharia AW, et al. The effect of a +-thalassaemia on the incidence of malaria and other diseases in children living on the coast of Kenya . PloS Med. 2006;3:e158. doi: 10.1371/journal.pmed.0030158. : 

Α-Thalassaemia and MalariaWambua S, Mwangi TW, Kortok M, Uyoga SM, Macharia AW, et al. The effect of a +-thalassaemia on the incidence of malaria and other diseases in children living on the coast of Kenya . PloS Med. 2006;3:e158. doi: 10.1371/journal.pmed.0030158. α +-thalassaemia did not protect against parasitisation in asymptomatic individuals. α +-thalassaemia did not protect against symptomatic malaria, nor did it lead to a reduction in the density of parasites in peripheral blood. In the birth cohort, there was reduced admission to hospital of α +-thalassaemic children with malaria or severe malaria. Thalassaemia provided no protection against cerebral malaria unless accompanied by anaemia—the protection by α +-thalassaemia appeared to be mainly confined to severe anaemia.

Hereditary Elliptocytosis and Southeast Asian ovalocytosis and Malaria : 

Hereditary Elliptocytosis and Southeast Asian ovalocytosis and Malaria Some mutation of elliptocytosis are due to glycophorin C deficiencies Plasmodium falciparum has a surface protein called erythrocyte-binding antigen 140, which is now known to bind to glycophorin C. Southeast Asian ovalocytosis reduce the capacity of the band 3 proteins to cluster together, thereby making it more difficult for the malaria parasite to properly attaching to and enter the cell.

Malaria and HIV disease in sub Saharan Africa : 

Malaria and HIV disease in sub Saharan Africa Malaria and HIV are leading causes of morbidity and mortality, particularly in sub Saharan Africa Both diseases are highly endemic and have a wide geographic overlap A small effect of malaria on HIV or vice-versa could have substantial population-level implications HIV Malaria

Malaria and HIV biologic interactions : 

Malaria and HIV biologic interactions HIV-associated immunosuppression contributes to more and worse malaria and it’s consequences in adults, pregnant women, and children. Malaria contributes to stimulus of HIV replication and possibly(?) to its consequences: disease progression, transmission in adults, and MTCT. Co-infection with Malaria and HIV in pregnant women contributes to anemia, low birth weight,and their risk for poor infant survival. Malarial anemia in children too frequently requires blood transfusion and may still lead to HIV transmission

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MALARIA – clinical syndromes Non-severe Acute Febrile disease Cerebral Malaria Death DR AHMED SAAD 2009

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Quartan malaria Benign Tertian malaria Malignant tertian malaria

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Etol Etiologies of Fever In Malaria

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Signs: Fever Jaundice Pallor Tachycardia Hypotension Splenomegaly Blackwater Fever Cerebral Malaria Hypoglycaemia should always be excluded Intravascular Haemolysis

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Early Diagnosis and prompt Treatment is necessary

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High Mortality Rate if Treatment is Delayed

Clinical features suggesting P. falciparum infection: : 

Clinical features suggesting P. falciparum infection: Presence of any of the complications of P. falciparum malaria viz. altered sensorium; convulsions; coma; jaundice; severe anemia; hypotension; prostration; hyperpyrexia; renal failure etc. Atypical presentation. Not responding to chloroquine therapy within 48 hours. Recurrence within 2 weeks.

P falciparum accounts for about 50% of cases but 95% of malarial deaths worldwide : 

P falciparum accounts for about 50% of cases but 95% of malarial deaths worldwide P vivax and P ovale infects only immature RBCs, leading to limited parasitemia The adhesion prevents the spleen from clearing diseased cells

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 Knobs of histidine rich proteins is the points of attachment to endothelial cells RBC with Plasmodium Falciparum infection

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Maurer's clefts PfEMP3 (blue) Trafficking of KAHRP to the knobs of P.falciparum-infected erythrocytes THE EMBO JOURNAL (2001) 20, 5636 - 5649 Parasitophorous vacuole (PV) ATP-dependent transporter

Why is falciparum malignant ? : 

Why is falciparum malignant ? Each cycle releases 20 times more merozoites than vivax Multiple infestation of both mature and immature RBC. P vivax and P ovale infects only immature RBCs, leading to limited parasitemia Early hemolysis and endotoxin release, cerebral toxicity Bilirubin load affects kidneys, liver Hypovolemia and shock occur Usually resistant to Chloroquine

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Plasmodium Falciparum:Hyperparasitaemia The parasites derive their energy solely from glucose, and they metabolize it 70 times faster than the RBCs they inhabit, thereby causing hypoglycemia and lactic acidosis.

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Multiple Organ Failure ARDS ATN Heart Liver

Cerebral Malaria : 

Cerebral Malaria Unrousable coma--no localizing response to pain persisting for more than six hours if the patient has experienced a generalized convulsion; asexual forms of P. falciparum found in blood; and exclusion of other causes of encephalopathy, i.e. viral or bacterial. (Newton and Warrell) The Blantyre Coma Scale, a related diagnostic tool, has been devised for young children. P. falciparum parasites in brain capillary Multiple hemorrhages Multiple hemorrhages Even with appropriate antimalarial therapy and intensive care, 15%–25% of patients die, and mortality may reach 50% if more than 10% of erythrocytes are parasitized

Malaria - Cytoadherence : 

Malaria - Cytoadherence Proteinaceous Knobs Cerebral Malaria

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Sequestration of RBC is unique to the pathogenesis of Plasmodium falciparum infection

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Sequestration of parasitized RBC in cerebral vessels

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Sequestration of cerebral capillaries and venules with parasitized red blood cells (PRBCs)

Sequestration of parasites and obstruction of brain vessels : 

Sequestration of parasites and obstruction of brain vessels The mechanical hypothesis asserts that a specific interaction between a P. falciparum erythrocyte membrane protein (PfEMP-1) and ligands on endothelial cells, such as ICAM-1 or E-selectin, reduces microvascular blood flow and induces hypoxia. This selective cytoadherence of PRBCs and non-PRBCs, also known as rosetting, can apparently better account for CM’s histopathological hallmark and its characteristic coma condition. However, this hypothesis is inadequate in explaining the relative absence of neurological deficit even after days of unconsciousness.

Humoral hypothesis for the explanation of the relative absence of neurological deficit even after days of unconsciousness. : 

Humoral hypothesis for the explanation of the relative absence of neurological deficit even after days of unconsciousness. The humoral hypothesis suggests that a malarial toxin may be released that stimulates macrophages to release TNF-a and other cytokines such as IL-1. The cytokines themselves are not harmful, but they may induce additional and uncontrolled production of nitric oxide. Nitric oxide would diffuse through the blood-brain barrier and impose similar changes on synaptic function as do general anesthetics and high concentrations of ethanol, leading to a state of reduced consciousness. The biochemical nature of this interaction would explain the reversibility of coma.

CT Findings for Cerebral Malaria : 

CT Findings for Cerebral Malaria 4 major patterns of CT brain findings that closely correlated with the clinical severity of malaria, as well as outcome. Normal CT findings Excellent prognosis; usually regain consciousness after anti-malarial therapy and without neurological deficit Diffuse cerebral edema Moderately severe malaria; Diffuse cerebral edema with bilateral thalamic hypoattenuation Severe malaria; survivors may have residual neurological deficit Diffuse cerebral edema with bilateral thalamic and cerebellar hypoattenuation Usually died

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Contrast-enhanced transverse CT scan obtained on day 1 in a 31-year-old female patient shows effacement of cerebral cortical sulci and compression of the body of the ventricles, suggestive of generalized cerebral edema. Tufail F. Patankar et al, September 2002 Radiology, 224, 811-816.

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Contrast-enhanced transverse CT scan of the brain in a 17-year-old male patient demonstrates bilateral thalamic hypoattenuation (arrows) with central areas of higher attenuation. (b) Follow-up transverse CT scan obtained on day 10 in same patient reveals residual thalamic hypoattenuation (arrows). Tufail F. Patankar et al, September 2002 Radiology, 224, 811-816.

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Contrast-enhanced transverse CT scan obtained in a 20-year-old male patient shows bilateral symmetric cerebellar hypoattenuation (arrows). (b) Contrast-enhanced transverse CT scan at the level of thalamus in the same patient at the same time demonstrates Tufail F. Patankar et al, September 2002 Radiology, 224, 811-816. In P. falciparum there is selective clogging of the cerebellar capillaries with parasitized red blood cells, which leads to microscopic infarcts, perivascular hemorrhages, shrinkage of the Purkinje cells, and perivascular clusters of microglia

Adjunctive measures for Cerebral Malaria Treatment : 

Adjunctive measures for Cerebral Malaria Treatment

Psychiatric Manifestation of Malaria(a) Altered behaviour, mood changes, hallucinosis or even acute psychosis, with or without fever(b) Improve completely with anti malarial therapy Mangalore, Nagesh Pai, Satish Rao and B.S. Kakkilaya : 

Psychiatric Manifestation of Malaria(a) Altered behaviour, mood changes, hallucinosis or even acute psychosis, with or without fever(b) Improve completely with anti malarial therapy Mangalore, Nagesh Pai, Satish Rao and B.S. Kakkilaya

Falciparum Hepatopathy : 

Falciparum Hepatopathy Kupffer cell hyperplasia and malarial pigment deposit

Causes of jaundice in malaria[Jaundice in malaria. Anand AC. Puri P. Journal of Gastroenterology & Hepatology. 20(9):1322-32, 2005 Sep.] : 

Causes of jaundice in malaria[Jaundice in malaria. Anand AC. Puri P. Journal of Gastroenterology & Hepatology. 20(9):1322-32, 2005 Sep.]

Two Form of Malarial Hepatitis Type B is a relatively benign condition while type A is associated with multi-organ failure. : 

Two Form of Malarial Hepatitis Type B is a relatively benign condition while type A is associated with multi-organ failure.

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90% of Malaria Deaths Occur Among Children Under Five Years of Age Most children in malaria endemic areas have first malaria infection during first two years of life before they acquire clinical immunity.

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*maximum estimate; all children <5 years of age except cerebral malaria (<10 years)

Presentation of severe malaria in the childrenWorldwide, the annual death toll of malaria exceeds 1 million, and children under the age of five are its major victims. : 

Presentation of severe malaria in the childrenWorldwide, the annual death toll of malaria exceeds 1 million, and children under the age of five are its major victims.

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Number One Priority For Control of Malaria in Children

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Three Effective Malaria Interventions can reduce all-cause child mortality by 20%-25% Promoting the use of insecticide-Rx mosquito nets Preventing & controlling malaria during pregnancy Providing prompt access to curative treatment

WHO recommendation for control of MIP in high/moderate malaria transmission area : 

WHO recommendation for control of MIP in high/moderate malaria transmission area Insecticide-Treated Nets Effective Case Management Intermittent Preventive Treatment (IPT) Anemia prevention

Malaria during pregnancyhigh/moderate transmission area : 

Malaria during pregnancyhigh/moderate transmission area Asymptomatic Infection Nutrient Transport Placental Sequestration Low Birth Weight Risk of Infant Mortality P. falciparum malaria Maternal Anemia

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P. Falciparum infestation with monocytosis containing haemozoin pigement in vessels of placenta.

The proposed influence of differences in thrombomodulin levels on cytokine-induced expression of adhesion molecules on endothelial cells, and monocyte attraction, in different organs. (a) tissues with low endothelial thrombomodulin levels (b) tissues with high levels.[Clark et al. Malaria Journal 2006 5:85] : 

The proposed influence of differences in thrombomodulin levels on cytokine-induced expression of adhesion molecules on endothelial cells, and monocyte attraction, in different organs. (a) tissues with low endothelial thrombomodulin levels (b) tissues with high levels.[Clark et al. Malaria Journal 2006 5:85]

WHO recommendation for control of MIP in high/moderate malaria transmission area : 

WHO recommendation for control of MIP in high/moderate malaria transmission area SP (1500 mg sulfadoxine, 75 mg pyrimethamine) 2 doses of IPT with SP is associated with: Reduction in 3rd trimester maternal anemia Reduction in placental malaria parasitemia Reduction in low birth weight At least 2 doses required for optimal benefit Regimen is safe and well tolerated Not recommended in HIV+ women receiving daily CTX

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Intermittent preventive treatment (IPTp) Pregnancy Fetal growth velocity  1 2 3 4 Schedule of 4 ANC visits for normal pregnancy First visit before quickening where LLIN (long lasting insecticidal nets) is given Three visits after quickening and IPTp given at each scheduled ANC (but not more frequently than monthly interval)

Pregnant women attract at least twice as many mosquitoes as non-pregnant patients.Preterm delivery, IUGR, abortion, stillbirth, eclampsia postpartum hemorrhage, puerperal fever, and maternal/fetal death are some complications associated with malaria particularly with P. falciparum. : 

Pregnant women attract at least twice as many mosquitoes as non-pregnant patients.Preterm delivery, IUGR, abortion, stillbirth, eclampsia postpartum hemorrhage, puerperal fever, and maternal/fetal death are some complications associated with malaria particularly with P. falciparum. Risk factors for adverse outcomesof women infected with malaria during pregnancy include HIV + status, low parity, non-immune, suboptimal treatment, and pregnancy during high transmissionseason.

Hypoglycemia and lactic acidosis due to malaria is seven times more frequent in pregnancy than in a non-pregnant woman. : 

Hypoglycemia and lactic acidosis due to malaria is seven times more frequent in pregnancy than in a non-pregnant woman. Cerebral malaria is a common presentation in pregnant patients. Particularly concerning is the increased case-fatality rate of cerebral malaria in pregnant patients of up to 50%. Case-fatality rates is approximately 20%, and 3% of patient develop permanent neurologic sequelae.

Clinical Features Of Severe Malaria In Pregnant Women : 

Clinical Features Of Severe Malaria In Pregnant Women Pregnant women are more prone to develop multiple complications of malaria. There are several factors that make pregnant women more vulnerable to malaria and its complications including mortality. Malaria parasites are preferentially sequestrated in the placenta, Acquired immunity against malaria is known to decline during pregnancy. During the second half of pregnancy, there is a transient immuno-suppression due to high levels of adrenal steroids, chorionic gonadotrophin, alpha-fetoprotein and depression of the role of lymphocytes. Therefore the incidence of malaria relapses, recrudescence & severe malaria is more common during pregnancy. Frequency of heavy parasitemia is more during pregnancy than in the non-pregnant state. Primigravidae are at higher risk of morbidity & mortality from malaria. Severe malaria poses a special problem as placental parasitemia is often associated with pregnancy rather than peripheral parasitemia. They usually have a multitude complications viz. severe anemia, hypoglycemia, acute renal failure, acute pulmonary oedema, ARDS. Risk of mortality is nearly three times higher than nonpregnant women. Associated infections: e.g. Urinary tract infections and respiratory tract infections, septicaemia are more common in the gravid state.

Malaria Complicating Pregnancy : 

Malaria Complicating Pregnancy Anaemia : Moderate or severe anaemia is associated with increased morbidity & mortality in pregnant women due to an increased risk of perinatal mortality, maternal morbidity, PPH and pulmonary oedema. Cerebral malaria- Although incidence of cerebral malaria is same as that of non-pregnant women, however once they develop cerebral malaria, the mortality is three times higher in pregnant women. Hypoglycemia - This may be present in pregnant women at the time of admission or may develop after quinine infusion. Commonly it is asymptomatic. Abnormal behaviour, sweating & sudden loss of consciousness are the usual manifestations. It may be associated with lactic acidosis, a dreaded accompaniment with mortality upto 70%. Women in second or third trimester of pregnancy may develop hypoglycemia even with low parasitemia. Pulmonary oedema : This is a serious complication. It may be present on admission, may develop unexpectedly several days later or may develop immediately after childbirth. Premature labour: In non immunised females, foetal distress and premature labour is common and may occur at the height of fever. Foetal prognosis with premature labour is invariably poor. In endemic areas, pregnant women tolerate heavy parasitemia better than the pregnant women from non endemic areas. Septicaemia: Pregnancy increases susceptibility to pneumococcal infections and may lead to pneumonia or meningitis. Septicaemia following bladder catheterisation is common in pregnant women with heavy parasitemia.

Safety Of Antimalarials During Pregnancy : 

Safety Of Antimalarials During Pregnancy Quinine does not cause abortion in therapeutic dose. The uterine contraction is related to the height of the fever and heavy parasitemia. Hence intravenous and oral quinine can be safely used in all trimesters of pregnancy. Artimisinin derivatives are not recommended at present, since extensive trials have not yet been conducted in pregnant women. Chloroquin is safe in all trimesters of pregnancy. Mefloquin is safe during pregnancy Sulfa containing drugs are contraindicated. Tetracycline and primaquin are contraindicated in pregnancy.

The rationale of Home Management of Malaria : 

IER rounds, 3 April 2009 The rationale of Home Management of Malaria Prompt and effective treatment of uncomplicated malaria prevents evolution to severe malaria and death Cure rate of ACTs in HMM is high (>90%)

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Made available close to the home through a network of trained community-based providers Backed up by a communication strategy for behaviour change Effective, pre-packaged, user-friendly, unit-dosed, antimalarials (ACTs)

Diagnosis of Malaria : 

Diagnosis of Malaria

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High index of suspicion is required

Before reporting a negative result, at least 200 oil immersion visual fields at a magnification of 100x should be examined on both thick and thin smears, which has a sensitivity of 90%. : 

Before reporting a negative result, at least 200 oil immersion visual fields at a magnification of 100x should be examined on both thick and thin smears, which has a sensitivity of 90%. One negative blood smear makes the diagnosis of severe malaria very unlikely; however, smears should be repeated every 12 hours for 48 hours if malaria is still suspected.

PlasmodiumFalciparum : 

PlasmodiumFalciparum In falciparum malaria, parasitized erythrocytes may be sequestered in tissue capillaries resulting in a falsely low parasite count in the peripheral blood ('visible' parasitemia). In such instances, the developmental stages of the parasite seen on blood smear may help to assess disease severity better than parasite count alone. The presence of more mature parasite forms (>20% of parasites as late trophozoites and schizonts) and of more than 5% of neutrophils containing malarial pigment indicates more advanced disease and a worse prognosis.

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Binax NOW is the only brand of malaria RDT approved for use in the united States. (CDC) Inability to detect P. ovale and P. malariae. P. falciparum LDH has L-malate dehydrogenase activity.

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Thick Smear Thin Smear

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Bananna/Crescent shape

Plasmodium falciparum : 

Plasmodium falciparum

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Malarial merozoites inside and outside RBC.

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RBCs infected with trophozoites do not produce sequestrins and are able to pass through the spleen.

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A mature schizont would secrete sequestrins protein on RBC surface enhancing its bounding to endothelial cells and subsequent sequestration in the spleen.

Falciparum gametocytes : 

Falciparum gametocytes Male Female

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Infected RBCs larger than non-infected RBCs, Schüffner’s dots

P. vivax : 

P. vivax

Differentiation of falciparum : 

Differentiation of falciparum P.falciparum trophozite P.vivax trophozite

Differentiation of falciparum : 

Differentiation of falciparum P.falciparum shizont P.vivax shizont

Differentiation of falciparum : 

Differentiation of falciparum P.falciparum gametocyte P.vivax gametocyte

P. ovale : 

P. ovale

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Infected RBCs same size as non-infected RBCs, No Schüffner’s dots Daisy head appearance

P. malariae : 

P. malariae

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Proguanil, dapsone Pyrimethamine–sulfadoxine targets the cytosolic folate biosynthetic pathway. Chloroquine, quinine amodiaquine and mefloquine interferes with the process of haem detoxification in the food-vacuole Atovaquone inhibits the mitochondrial electron transport chain Triclosan and thiolactomycin inhibit apicoplast fatty acid synthesis, while fosmidomycin targets the apicoplast-based DOXP pathway. Ciprofloxacin prevents the replication of the apicoplast genome and rifampicin acts upon apicoplast RNA transcription. Clindamycin seems to act upon apicoplast protein translation, while Doxycycline appears to inhibit both apicoplast and mitochondrial protein translation. Site of Action of Anti-malarial Drug Primaquine create oxygen free radicals that interfere with the plasmodial electron transport chain during respiration. Artemisinins causes toxic alkylation of heme in food vacuole Glyphosate inhibits a cytosolic shikimate pathway (aromatic acid synthesis in plant)

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Hemozoin An erythrocyte filled with merozoites Hemozoin, or malaria pigment, is a paracrystalline precipitate formed when heme polymerase reacts with eme stored within the erythrocyte. Chloroquine inhibit heme polymerase is inhibited, leading to the heme-induced destruction of non–chloroquine-resistant merozoites.

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Hemozoin crystals in the food vacuole of the malaria parasite

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Hemozoin

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Malarial fever: Hemozoin is involved but Toll-free Chloroquin interferes with both hemozoin formation and nuclease activity and intracellular TLR9 processing by blocking endosomal acidification.

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Role of CpG oligonucleotide–TLR9 interaction

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4-aminoquinolines Quinoline-alcohols Side Effects: Gastrointestinal Neuropsychiatric Pneumonitis

Cinchona calisaya (Quinine Tree) : 

Cinchona calisaya (Quinine Tree)

The Mechanism of Accumulation of Chloroquine in the Parasite Food Vacuole. Chloroquine travels down a pH gradient and inside the parasite becomes diprotonated. This form of the drug (shown in blue) is impermeable to biological membranes. On the right of the figure is a generic structure of a parasite targeted artemisinin derivative : 

The Mechanism of Accumulation of Chloroquine in the Parasite Food Vacuole. Chloroquine travels down a pH gradient and inside the parasite becomes diprotonated. This form of the drug (shown in blue) is impermeable to biological membranes. On the right of the figure is a generic structure of a parasite targeted artemisinin derivative

Slide 143: 

The major action of chloroquine(CQ) is to inhibit the formation of hemozoin (Hz) from the heme released by the digestion of hemoglobin (Hb). The free heme then lyses membranes and leads to parasite death. Chloroquine resistance is due to a decreased accumulation of chloroquine in the food vacuole by pfCRT mutant. Chloroquine concentrates up to several 1000-fold in the food vacuole of the parasite Reactive Oxygen Species pfCRT mutant

Slide 144: 

PfCRT actively pumps drug molecules out of the target area, rendering them ineffective Malaria: Big killer and big advancesThomas Wellems (NIAID) and John Robbins (NICHD)

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Malaria: Big killer and big advancesThomas Wellems (NIAID) and John Robbins (NICHD)

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The global distribution of malaria, showing areas where Plasmodium falciparum resistance to the most commonly used antimalarial drugs, chloroquine and sulphadoxine-pyrimethamine First Report of Drug Resistant

Slide 147: 

Gene cg2 PfCRT mutation Malaria: Big killer and big advancesThomas Wellems (NIAID) and John Robbins (NICHD)

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Malaria: Big killer and big advancesThomas Wellems (NIAID) and John Robbins (NICHD) 100% Selection of K76T mutant Djimde et al. N Engl J Med 2001;344(4):257-263

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Malaria: Big killer and big advancesThomas Wellems (NIAID) and John Robbins (NICHD) Evolutionary and Historical Aspects of the Burden of Malaria Richard Carter1* and Kamini N. Mendis2 Clinical Microbiology Reviews, October 2002, p. 564-594, Vol. 15, No. 4

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Malaria: Big killer and big advancesThomas Wellems (NIAID) and John Robbins (NICHD) Impact of chloroquine resistance on malaria mortality C R Acad Sci III 1998, 321:689-697 Sokhna CS, Molez JF, Ndiaye P, Sane B, Trape JF

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Chloroquine-resistant malaria 2001: Wellems T E; Plowe C V The Journal of infectious diseases 2001;184(6):770-6. Immunity and Chloroquine Treatment Outcome

Slide 152: 

Malaria: Big killer and big advancesThomas Wellems (NIAID) and John Robbins (NICHD) CLEARANCE OF DRUG-RESISTANT PARASITES AS A MODEL FOR PROTECTIVE IMMUNITY IN PLASMODIUM FALCIPARUM MALARIA ABDOULAYE A. DJIMDÉ Am. J. Trop. Med. Hyg., 69(5), 2003, pp. 558-563

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Malaria: Big killer and big advancesThomas Wellems (NIAID) and John Robbins (NICHD)

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Malaria: Big killer and big advancesThomas Wellems (NIAID) and John Robbins (NICHD)

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Malaria: Big killer and big advancesThomas Wellems (NIAID) and John Robbins (NICHD) Chloroquine Structure and Activity Relationship

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Malaria: Big killer and big advancesThomas Wellems (NIAID) and John Robbins (NICHD)

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PfCRT Mutation and Chloroquine Response Role of Amantadine for Chloroquine-R Malaria [Thomas E Wellems1 Nature Medicine 10, 1169 - 1171 (2004)] Wild-type parasites carrying PfCRT Lys76 PfCRT mutation confer cloroquine- R Amantadine reverse chloroquine resistance I356V Mutant

Slide 158: 

Amantadine potentiated the effect of chloroquine and quinine in both CR and CS strains; it also potentiated the effect of mefloquine, halofantrine and primaquine in the chloroquine-resistant strain but had no effect in the chloroquine-sensitive strain. Amantadine had no effect on the response to pyrimethamine of either strain. Amantadine does not interfere with the activity of these compounds and may possibly enhance it. In vitro drug interaction between amantadine and classical antimalarial drugs in Plasmodium falciparum infections Sandra Gail Evans, Ivan Havlik Volume 88, Issue 6, Pages 683-686 (November 1994) Effective for both chloroqine sensitive (CS) and resistant (CR) strains

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A verapamil-sensitive chloroquine-associated H+ leak from the digestive vacuole in chloroquine-resistant malaria parasites.Lehane AM. Hayward R. Saliba KJ. Kirk K. Journal of Cell Science. 121(Pt 10):1624-32, 2008 May 15. The chloroquine-associated increase in the rate of alkalinisation seen in chloroquine-resistant parasites was inhibited by the chloroquine-resistance reversal agent verapamil.

Slide 160: 

PfCRT actively pumps drug molecules (e.g. chloroquine) out of the target area, rendering them ineffective. Tricyclic acridone molecules with a short alkyl amine chain attached to the central nitrogen atom could make chloroquine-resistant parasites susceptible to the drug again. This action is attributed to blocking the PfCRT pump protein, meaning that the chloroquine can reach its target.  (J X Kelly et al, Nature, 2009.)

Slide 162: 

The Breakthrough of anti-malaria therapy An ancient drug in China REDISCOVERED Artemesia annua or Chinese wormwood (中草药青篙,学名黄花篙)  artemisinin (青蒿素)),

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"Fifty-two Prescriptions" of Artemisia annua (annual wormwood),青蒿 from the Mawangdui Han Dynasty Tombs 200 B.C. unearthed.

瘧 (Nüe) Intermittent Fever : 

瘧 (Nüe) Intermittent Fever Materia medica =>青蒿 Qinghao Ge Hong 284–363 肘後備急方Emergency Prescriptions to Keep up your Sleeve Treatment of intermittent fever ‘Another recipe: qinghao, one bunch, take two sheng [2 × 0.2 l] of water for soaking it, wring it out (擰乾 ) take the juice, ingest it in its entirety’ 屠呦呦 To Youyou Dihydroartemisinin Artemisinin is water insoluble Artemisia annua

Artemisinin is naturally-occurring endoperoxide sesquiterpene lactone : 

Artemisinin is naturally-occurring endoperoxide sesquiterpene lactone

Artemisinins Derivatives : 

Artemisinins Derivatives Artemisinin derivatives Methyl Ether Hemisuccinate Ethyl Ether Arteether Artemether Artesunate Dihydroartemisin Qinghaosu ("ching-how-soo")

Some features of CF3-DHA : 

Some features of CF3-DHA Dihydroartemisin

Slide 170: 

No hypnozoiticidal activity High valent iron-oxo species damage food vacuoles membrane Depolarization of the mitochondrial membrane

Artesunate should not be used during the first trimester of pregnancy. : 

Artesunate should not be used during the first trimester of pregnancy. After parenteral administration, artesunate is rapidly hydrolyzed to the active metabolite dihydroartemisinin. The oral formulation is probably hydrolysed completely before entering the systemic circulation. Peak serum levels occur within one hour of an oral dose with elimination half-life of 45 minutes. Artesunate has a minimal effect on hepatic cytochrome P450 activity and does not appear to influence the metabolism of mefloquine, a drug likely to be used in combination with artesunate. Artersunate does not inhibit the formation of carboxy-primaquine, a metabolite of primaquine. Artesunate is water-soluble hemisuccinate derivative of dihydroartemisinin - Available in oral, IVI, IMI and PR form

IV Administration of Artesunate : 

IV Administration of Artesunate Step. 1 : The powder for injection should be reconstituted with 1ml of 5% sodium bicarbonate and shaken vigorously till the solution becomes clear. Step 2 : For I.V. use, add 5 ml (2ml for I.M. use) of normal saline or 5% of glucose and mix again. Step 3 : For I.V. use, the required amount of the drug is administered slowly over a period of 2 - 3 minutes. The powder for Injection is difficult to dissolve and care should be taken to ensure that it is completely dissolved before parenteral administration. It should always be used immediately after reconstitution. If the solution is cloudy or a precipitate is present, the parenteral preparation should be discarded. The speed for intravenous injection is 3-4 ml per minute.

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Cardiovascular effects of intravenously administered antimalarial drugs[Cardiotoxicity of antimalarial drugs. White NJ. The Lancet Infectious Diseases. 7(8):549-58, 2007 Aug.]

Cardiovascular effects of orally administered antimalarial drugs : 

Cardiovascular effects of orally administered antimalarial drugs

Pharmaceutical Preparations of Artemisinin Derivatives for Rectal Administration [Karunajeewa: JAMA, Volume 297(21).June 6, 2007.2381–2390] : 

Pharmaceutical Preparations of Artemisinin Derivatives for Rectal Administration [Karunajeewa: JAMA, Volume 297(21).June 6, 2007.2381–2390]

Artemisinin-based Combination Therapy (ACT)A Major Breakthrough in Anti-malarial Therapy : 

Artemisinin-based Combination Therapy (ACT)A Major Breakthrough in Anti-malarial Therapy Rationale for ACT Resistance to Chloroquine and sulphadoxine-pyrimethamine Protect individual drug from resistance To decrease rate of decline in efficacy To interrupt spread of resistant strains To decrease transmission in a region The combination is often more effective In the rare event of resistance to one of the drugs during the course of the infection, the parasite will be killed by the other drug

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Artemisinin-based Combination Therapy (ACT) A Major Breakthrough in Anti-malarial Therapy

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Second line Combinations Therapy

Unit-dose packaged drugs for treating malaria. Orton L. Barnish G. Cochrane Database of Systematic Reviews. (2):CD004614, 2005.] : 

Unit-dose packaged drugs for treating malaria. Orton L. Barnish G. Cochrane Database of Systematic Reviews. (2):CD004614, 2005.] Blister-packed artesunate and mefloquine (from Cambodia) Blister-packed artemether-lumefantrine (trade name Coartem, Novartis) Blister-packed sulfadoxine-pyrimethamine and amodiaquine (from Rwanda) Sectioned polythene bags of chloroquine (from Ghana)

Lumefantrine : 

Lumefantrine Schizonticidal; Safe in pregnancy AMMS – China discovered it 1970 Registered for use in 1987 Half life 3-6 days Lumefantrine binds to toxic haemin (FP9) that is produced in the course of haemoglobin digestion the food vacuole of parasite. The binding prevents the polymerisation of haemin to non-toxic malaria pigment. The absorption of lumefantrine is dependent on the presence of food in the stomach, which can be difficult as loss of appetite and nausea are frequent during malaria attacks. Intake of about 1.5 g of fat seems sufficient for satisfactory absorption. Unlike halofantrine, it has no significant effect on the QT interval.

AL Dosage Schedule : 

AL Dosage Schedule Artemether-Lumefantrine (Coartem, Lumether, Riamet)

AL Dosage Schedule : 

AL Dosage Schedule Artemether-Lumefantrine (Coartem, Lumether, Riamet)

What to give in pregnancy ? : 

What to give in pregnancy ? In 1st trimester Quinine + Clindamycin 7 days In 2nd and 3rd trimesters Any ACT combination as per rec. or Artesunate + Clindamycin 7 days or Quinine + Clindamycin 7 days Lactating women same ACT

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AM

MALARIAManagement Guideline : 

MALARIAManagement Guideline

MALARIAManagement Guideline : 

MALARIAManagement Guideline

Management of Acute Attack : 

Management of Acute Attack Anti-malarial chemotherapy should be administered as soon as the diagnosis is made Monitor blood for parasites and repeat testing is needed if the diagnosis is strongly suspected Maintain fluid and electrolytes balance; avoid overhydration Renal failure regime for blackwater fever; treat hypoglycaemia and/or shock if present Pulmonary oedema may develop, treated by prop up, oxygen,loop diuretic, venodilator; if hypoxic may need positivepressure ventilation Avoid sedatives and corticosteroids Watch for relapse (usually within 2 months) and signs of peritoneal irritation (splenic rupture)

Anti-malarial Chemotherapy for Uncomplicated P. vivax, P. malariae and P. ovale : 

Anti-malarial Chemotherapy for Uncomplicated P. vivax, P. malariae and P. ovale Chloroquine 600 mg base po stat and 300 mg base 6 hours later then 300 mg base daily for 2 more days plus Primaquine 15 mg base (0.25 mg/kg) po daily taken with food for 14 days in P. vivax and P. ovale infection to eradicate hypnozoites in the liver NOTE 1 Chloroquine-resistant P. vivax reported from Oceania and South America, Mefloquine 750 mg po, then 500 mg 12 hours later NOTE 2 Primaquine-resistant P. vivax reported in South-east Asia and Western Pacific. An increased of the dose to 22.5 – 30 mg daily (or 0.5 mg/kg) is effective NOTE 3 Primaquine is contraindicated in pregnancy. In G6PD deficiency, primaquine is safe in dosage of 30 mg once a week for 8 weeks. Monitor Hb level.

Uncomplicated P. falciparum malaria : 

Uncomplicated P. falciparum malaria Definition: symptomatic malaria without signs of severity or evidence of vital organ dysfunction Treatment: a. Artesunate 200 mg (4 mg/kg) po daily for 3 days plus Mefloquine 1000 mg base po on day 2, then 500 mg po on day 3 b. Quinine 600 mg salt (10 mg/kg) po 8 hourly for 7 days plus Doxycycline 100 mg po bid for 7 days

Severe P. falciparum malaria : 

Severe P. falciparum malaria Definition: presence of one or more of the following clinical or laboratory features, after excluding other obvious cause of their symptoms: Clinical: Prostration, Impaired consciousness, Respiratory distress (acidotic breathing), Multiple convulsions, Circulatory collapse,Pulmonary oedema (radiological), Abnormal bleeding, Jaundice,Haemoglobinuria Laboratory: Severe anaemia, Hypoglycaemia, Acidosis, Renal impairment, Hyperlactataemia, Hyperparasitaemia (>5%)

Treatment of Severe P. falciparum malaria : 

Treatment of Severe P. falciparum malaria a. Artesunate 2.4 mg/kg i.v. or i.m. given on admission (time = 0), then at 12 h and 24 h, then once a day until oral medication could be taken, treat for a total of 7 days plus Doxycycline 100 mg po bid for 7 days once oral medication could be taken or Mefloquine as in above section B2a b. Quinine dihydrochloride 20 mg/kg loading dose in 5% dextrose infused over 4 hours, maintenance dose 10 mg/kg infused over 2 – 4 hours every 8 hours. Change to oral dose when feasible to complete a 7-day course plus Doxycycline as in above section C2a Note 1 Consider Primaquine 45 mg single dose to eradicate gametocytes in blood at the end of treatment of falciparum malaria Note 2 Do not use loading dose if patient has received quinine,quinidine, or mefloquine in preceding 24 hours.

Exchange transfusion : 

Exchange transfusion CDC recommends that exchange transfusion be strongly considered for persons with a parasite density of more than 10% or if complications such as cerebral malaria, non-volume overload pulmonary edema, or renal complications exist. Its beneficial effect by removing infected red cells, improving the rheological properties of blood, and reducing toxic factors such as parasite derived toxins, harmful metabolites, and cytokines.

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36% counterfeit antimalarials

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Prevention is Better than cure Dusk to Dawn Feeders

Slide 206: 

Prevention of Mosquito Bites

Slide 207: 

Three Effective Malaria Interventions can reduce all-cause child mortality by 20%-25% $2.50 -- 5.00 Intermittent Preventive Tx in preg: $0.35 Malaria treatment: CQ, SP, AQ, Lap-Dap: $0.10 – 0.50 Artemisinin-combinations: $2.00 or more

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Insecticide-treated tarpaulins (天蓬及遮陽蓬)used for malaria prevention in a refugee camp in Sierra Leone.

Card for Travelers Who Expect to Be in Areas Endemic for Malaria : 

Card for Travelers Who Expect to Be in Areas Endemic for Malaria Malaria Information for Traveler You will be visiting countries with malaria and may be exposed to malaria, which can progress rapidly and kill. Ways to Reduce Risk Stay in accommodations with screens in windows and doors. Go indoors from dusk to dawn. Use an effective insect repellant, such as one that contains diethyltoluamide (DEET). Treat your clothing with insecticide, such as permethrin. Sleep under an insecticide-treated bed net. Take medication that suppresses malaria as recommended by a travel medicine specialist. If you tolerate malaria medication well, continue taking it even if others tell you there is no need. Symptoms of Malaria Symptoms may start as early as 7 to 8 days after exposure but may be delayed for weeks or months (rarely >1 year) after exposure. Symptoms include fever, which may be intermittent; body ache; weakness; headache; vomiting; abdominal pain; cough. Seek Medical Attention If you have any of the symptoms, seek medical evaluation as soon as possible, even if fever is not constant. Inform the clinicians that evaluate your fever that you may have been exposed to malaria. Check blood tests, including malaria smears, every 12 to 24 hours until at least 3 sets of smear results are negative for malaria.

ABCDE of Malaria For Travellers : 

ABCDE of Malaria For Travellers A – be AWARE of the risk B – avoid mosquito BITES Skin cover (wear long sleeves and long pants in tropical areas.) Use a DEET based repellent Knockdown sprays Screens, air conditioning and nets C – take your CHEMOPROPHYLAXIS (medication to help prevent malaria) D – DIAGNOSE quickly E – if more than 24hrs from medical attention take a course of EMERGENCY stand-by treatment

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Reasons why travelers fail to take chemoprophylaxis Incorrect belief that acquired immunity is maintained after leaving a malarious area Incorrect belief that some areas are free of malaria Don't know that resistance to chloroquine has developed Fears of drug side-effects

Malaria Vaccine : 

Malaria Vaccine

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Chloroquine-resistant malaria 2001: Wellems T E; Plowe C V The Journal of infectious diseases 2001;184(6):770-6. Immunity and Chloroquine Treatment Outcome

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Resistant genotype was more prevalent than in-vivo resistance is consistent with the view that acquired immunity contributes to parasite clearance Application of a molecular marker for surveillance of chloroquine-resistant falciparum malaria The Lancet, Volume 358, Issue 9285, Pages 890 - 891, 15 September 2001

Transmission intensity, incidence, and age : 

Transmission intensity, incidence, and age Dielmo, Senegal – 200 infections/year Ndiop, Senegal – 20 infections/year

Slide 219: 

Liver Stage Blood Stage Sporozoites Merozoites Gametocytes

Plasmodium life cycle and theoretical activity points of the different malaria vaccines. [Aide: Arch Dis Child, Volume 92(6).June 2007.476-479] : 

Plasmodium life cycle and theoretical activity points of the different malaria vaccines. [Aide: Arch Dis Child, Volume 92(6).June 2007.476-479]

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Liver Stage Sporozoites Pre-erythrocytic Stage

Pre-erythrocytic Stage Vaccines : 

Pre-erythrocytic Stage Vaccines How they work: Generates antibody response against sporozoites and prevents them from invading the liver Prevents intra-hepatic multiplication by killing parasite-infected hepatocytes Intended Use: Ideal for travelers - protects against malaria infection

Slide 223: 

Blood Stage Merozoites Asexual Erythrocytic Stage

Asexual Erythrocytic Stage Vaccines : 

Asexual Erythrocytic Stage Vaccines How they work: Elicit antibodies that will inactivate merozoites and/or target malarial antigens expressed on RBC surface Inhibit development of parasite in RBCs Intended Use: Morbidity reduction in endemic countries

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Gametocytes Sexual Stage

Sexual Stage Vaccines : 

Sexual Stage Vaccines How they work: Induces antibodies against sexual stage antigens Prevents development of infectious sporozoites in salivary glands of mosquitoes Prevent or decrease transmission of parasite to new hosts Intended Use: Decreased malaria transmission

Major malaria candidate vaccines in clinical development [Aide: Arch Dis Child, Volume 92(6).June 2007.476-479] : 

Major malaria candidate vaccines in clinical development [Aide: Arch Dis Child, Volume 92(6).June 2007.476-479]

Challenges for Malaria Vaccine : 

Challenges for Malaria Vaccine Four antigenetically distinct malaria species Each has ~6,000 genes First gene only identified in 1983 Immunity in malaria is complex and immunological responses and correlates of protection are incompletely understood. Identifying and assessing vaccine candidates takes time and is expensive There is no clear ‘best approach’ for designing a malaria vaccine

Slide 229: 

La Malaria (1850-1851), oil on canvas by French artist Antoine Auguste Ernest Hébert (1817-1908). Useful websites on malaria. Centers for Disease Control and Prevention http://www.cdc.gov/malaria/ World Health Organization http://www.who.int/topics/malaria/en/ The Malaria Foundation http://www.malaria.org Travel doctor http://www.traveldoctor.co.uk/tables.htm