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In 2700 BC, several characteristic symptoms of what would later be named malaria were described in the Nei Ching, Hippocrates and Malaria : Hippocrates and Malaria Hippocrates, a physician born in ancient Greece, today regarded as the "Father of Medicine", was the first to describe the manifestations of the disease, and relate them to the time of year and to where the patients lived. Malaria : Malaria Name is derived from Italian Mal’ aria or bad air Malaria continues to be most important cause of fever and morbidity in the Tropical world Malaria has been eradicated from Europe, Most of North America, USA South America Korea and Japan, Slide 5: Malaria-endemic Areas 2000 Why it is important in Medicine : Why it is important in Medicine Malaria remains the world's most devastating human parasitic infection. Malaria affects over 40% of the world's population. WHO, estimates that there are 350 - 500 million cases of malaria worldwide, of which 270 - 400 million are Falciparum malaria, the most severe form of the disease. Malaria Kills more people than AIDS : Malaria Kills more people than AIDS Malaria kills in one year what AIDS kills in 15 years. For every death due to HIV/AIDS there are about 50 deaths due to malaria. To add to the problem is the increasing drug resistance to the established drug. History – Events on Malaria : History – Events on Malaria 1880 - Charles Louis Alphose Lavern discovered malarial parasite in wet mount 1883 - Methylene blue stain - Marchafava 1891 - Polychrome stain- Romanowsky 1898 - Roland Ross - Life cycle of parasite transmission, wins Nobel Prize in 1902 1948 - Site of Exoerythrocytic development in Liver by Shortt and Garnham Major Developments in 20th Century : Major Developments in 20th Century 1955 - WHO starts world wide malaria eradication programme using DDT 1970 – Mosquitos develop resistance to DDT Programme fails 1976 – Trager and Jensen in vitro cultivation of parasite Charles Louis Alphonse Laveran, : Charles Louis Alphonse Laveran, Charles Louis Alphonse Laveran, a French army surgeon stationed in Constantine, Algeria, was the first to notice parasites in the blood of a patient suffering from malaria. This occurred on the 6th of November 1880. For his discovery, Laveran was awarded the Nobel Prize in 1907. Doctortvrao’s ‘e’ learning series Ronald Ross : Ronald Ross In August 20th, 1897, Ronald Ross, a British officer in the Indian Medical Service, was the first to demonstrate that malaria parasites could be transmitted from infected patients to mosquitoes For his discovery, Ross was awarded the Nobel Prize in 1902. Doctortvrao’s ‘e’ learning series Nobel Prizes in Malaria : Nobel Prizes in Malaria The discovery of this parasite in mosquitoes earned the British scientist Ronald Ross the Nobel Prize in Physiology or Medicine in 1902. In 1907, Alphonse Lavern received the Nobel prize for his findings that the parasite was present in human blood. Chloroquine (Resochin) (1934, 1946) : Chloroquine (Resochin) (1934, 1946) Chloroquine was discovered by a German, Hans Andersag, in 1934 at Bayer I.G. Farbenindustrie A.G. laboratories in Eberfeld, Germany. He named his compound resochin. Through a series of lapses and confusion brought about during the war, chloroquine was finally recognized and established as an effective and safe antimalarial in 1946 by British and U.S. Doctortvrao’s ‘e’ learning series Malaria a vector borne Disease : Malaria a vector borne Disease Malaria is a vector-borne infectious disease caused by protozoan parasites. It is widespread in tropicl and subtropical regions, including parts of the Americas, Asia, and Africa. Female Anopheles Mosquitos transmit Malaria : Female Anopheles Mosquitos transmit Malaria Parasites Cause of Malaria : Parasites Cause of Malaria Malaria is caused by an infection by one of four single celled Plasmodia species, they are: falciparum, vivax, malariae, and ovale. The most dangerous of the four is.P.falciparum Newer species : Newer species A fifth species, Plasmodium knowlesi, causes malaria in macaques but can also infect humans. Doctortvrao’s ‘e’ learning series SPOROZOA : SPOROZOA SPOROZOA belong to phylum Apicomplexa – contains two classes 1 Haematozoea 2 Coccidea Belong to class Haematozoea occur in the blood of the vertebrate hosts contain two orders Haemosporidia (genus Plasmodium – Malaria ) Piroplasmidia (containing genus Babesia) Doctortvrao’s ‘e’ learning series Structure of Malarial parasite : Structure of Malarial parasite Falciparum most Dangerous : Falciparum most Dangerous Falciparum accounts for 90% of deaths due to malaria and vivax is the most widely spread species because it exists in both temperate and tropical climates (Encarta). The malaria life cycle is a complex system with both sexual and asexual aspects . Doctortvrao’s ‘e’ learning series A complex Life cycle : A complex Life cycle Human Cycle : Human Cycle 1 Pre erythrocytic schizogony 2 Erythrocytic Schizogony 3 Gametogony 4 Exoerythrocytic schizogony Doctortvrao’s ‘e’ learning series Events in Humans start with Bite of Mosquito : Events in Humans start with Bite of Mosquito Man – Intermediate host. Mosquito – Definitive host – Sporozoites are infective forms Present in the salivary gland of female anopheles mosquito After bite of infected mosquito sporozoites are introduced into blood circulation. Doctortvrao’s ‘e’ learning series Period of Pre erythrocytic cycle : Period of Pre erythrocytic cycle 1 P.vivax 8 days 2 P.falciparum – 6 days 3 P.malariae - 13 – 16 days, 4 P.ovale 9 days On maturation Liver cells ruputure Liberate Merozoites into blood stream Doctortvrao’s ‘e’ learning series Pre erythrocytic cycle : Pre erythrocytic cycle Sprozoites undergo developemtnal phase in the liver cell Sprozoites are elongated and spindle shaped become rounded inside the liver parenchyma Multiple nuclear divisions develop to Schozonts A Schizont contains 20,000 – 50,000 merozoites. Doctortvrao’s ‘e’ learning series Slide 28: Exo- erythrocytic (hepatic) cycle Malaria Life Cycle Life Cycle Schizogony Sporogony Exo-erythrocytic (tissue) phase : Exo-erythrocytic (tissue) phase P. malariae or P. falciparum sporozoites do not form hypnotizes, develop directly into pre-erythrocytic schizonts in the liver Pre-erythrocytic schizogeny takes 6-16 days post infection Schizonts rupture, releasing merozoites which invade red blood cells (RBC) in liver Affinity of Parasite to Erythrocytes : Affinity of Parasite to Erythrocytes P.vivax P.malariae Infectes only young or P.ovale Old Erythocytes P.falciparum Infects all age groups Also adhere to the endothelial lining of Blood vessesl Causes the obstruction, Thrombosis and Local Ischemias Erythrocyte cycle : Erythrocyte cycle Merozoites released invade red cells P.vivax infects young erythrocytes P.malariae Infects old erythrocytes P.falciparum infects RBC of all ages The Merozoites are pear shaped 1-5 microns in length The receptors for Merozoites are on red cells in the glycoprotein Doctortvrao’s ‘e’ learning series Erythrocytic Schizogony : Erythrocytic Schizogony Liberated Merozoites penetrate RBC Three stages occur 1 Trophozoites 2 Schizont 3 Merozoite Erythrocytic cycle : Erythrocytic cycle Ruptured red cells release Merozoites which attack new red cells Continue with Schizogony Repeated cycles will continue In P.falciparum - infected erythrocytes with Schizonts aggregate in the capillaries of brain and other internal organs Only ring forms are seen in the blood smears Trophozoites : Trophozoites After invasion grow and feed on hemoglobin Blue cytoplasm and red nucleus, Called as Signet ring appearance Hence called ring form Schizont : Schizont When the Trophozoite is fully developed becomes compact. Malarial pigments are scattered through the cytoplasm The Nucleus is large and lies at the periphery starts dividing. Becomes Schizont Doctortvrao’s ‘e’ learning series Plasmodium vivax : Plasmodium vivax Number of merozoites 12 to 24 arranged in grape like clusters RBC enlarged Schuffner’s dots present Yellowish brown fine granules Schizont 9-10 microns fills and enlarged Red cell Gametocytes – spherical or globular Size much larger than red cell Male 9 microns Female 10 – 11 microns Doctortvrao’s ‘e’ learning series Plasmodium falciparum : Plasmodium falciparum RBC is normal size Maurer’s dots 9 large red spots sometimes basophilic stippling Dark brown or blackish one or two solid blocks Gametocytes Crescentric, larger than a red cell 9 -10 microns, male and female 12- 14 microns Plasmodium malaria : Plasmodium malaria RBC Normal size Contain Ziemann’s stippling Contain dark brown coarse granules Schizont – 6 – 7 microns almost fills a normal sized red cell. Gametocytes Spherical or globular Size much larger than a red cell Plasmodium ovale : Plasmodium ovale Infected RBC slightly larger Contain Schuffner’s dots coarse granules Schizont 6.2 microns fills three quarters Merozoites 6 -12 fills three quarters Gametocytes Spherical or globular, much larger than a red cell Doctortvrao’s ‘e’ learning series Exo-erythrocytic (tissue) phase : Exo-erythrocytic (tissue) phase P. malariae or P. falciparum sporozoites do not form hypnozites, develop directly into pre-erythrocytic schizonts in the liver Pre-erythrocytic schizogeny takes 6-16 days post infection Schizonts rupture, releasing merozoites which invade red blood cells (RBC) in liver Exo Erythrocytic Schizogony : Exo Erythrocytic Schizogony Some Sprozoites do not undergo sporogony in the first instance But go into resting stage called as Hypnozoites,( hibernation ) Within 2 years reactivate to form Schizonts release Merozoites and attack red cell and produce relapses Absent in P falciparum Doctortvrao’s ‘e’ learning series Gametogony : Gametogony Merozoites differentiate into Male and female gametocytes Macrogametocytes also called female gametocytes Microgametocyte also called as male gametocytes They develop in the red cells Found in the peripheral blood smears Microgametocyte of all species are similar in size Macro gametocytes are larger in size. Mosquito cycleA definitive Host – Mosquito : Mosquito cycleA definitive Host – Mosquito Mosquito cycleSexual cycle : Mosquito cycleSexual cycle Sexual cycle will be initiated in the Humans by the formation of Gametocytes Develop further in the female Anopheles Mosquito Only mature sexual forms are capable of further development in Mosquito In midgut one Microgametocyte develops into 4-8 thread like filamentous structures named Micro gametes From one macrogametocyte only one macrogamete is formed Events in Mosquitos : Events in Mosquitos Fertilization occurs when a Microgametocyte penetrate into Macrogametocyte Fertilized macrogametocyte is known as ZYGOTE ZYGOTE matures into OOKINETE OOKINETE to OOCYST Formation of Sporozoites in Mosquitos. : Formation of Sporozoites in Mosquitos. OOCYST matures with large number of Sporozoites ( A few hundred to thousands.) OOCYST ruptures and release SPOROZOITES in the body cavity of Mosquito There is a specific predilection for salivary glands Now capable to transmit the infection to new Host Doctortvrao’s ‘e’ learning series Pathology and Pathogenesis : Pathology and Pathogenesis Sporozoites result from sexaul and sporogenic cycle of development in mosquitoes and injected into human blood serum. Events start with bite of Infected Anopheles Mosquitoes Sporoozoites enter liver, in 1 hour infect the parenchymal cell. Pathology and Pathogenesis : Pathology and Pathogenesis Sporozoites result from sexaul and sporogenic cycle of development in mosquitoes and injected into human blood serum. Events start with bite of Infected Anopheles Mosquitoes Sporoozoites enter liver, in 1 hour infect the parenchymal cell. Pathogenesis in Pre Erythrocyte cycle : Pathogenesis in Pre Erythrocyte cycle Numerous asexual progeny – Merozoites ruputure and leave from liver cells Enter the Blood and invade Erythrocytes Erythrocytic cycle starts – Multiply in species specific fashion Broods of Merozoites appearing at 48 hour interval in P.ovale, P.vivax , P.falciparum P.malariae appear in 72 hour cycles, Chooses to enter the RBC : Chooses to enter the RBC Specific for each species They pit on red cells By endocytosis enters the RBC Becomes a Trophozoites Schizont : Schizont When the Trophozoite is fully developed becomes compact. Malarial pigments are scattered through the cytoplasm The Nucleus is large and lies at the periphery starts dividing. Becomes Schizont Doctortvrao’s ‘e’ learning series Cycles differs in Different species : Cycles differs in Different species Cycle repeats every 48 hours in 1 P.falciparum 2 P.ovale 3 P.vivax Repeats every 72 hours In P.malariae Doctortvrao’s ‘e’ learning series Incubation period varies according to species : Incubation period varies according to species Which includes Exo eythrocytic cycle time and one or two erythocytic cycles, P.vivax and P.falciparum 10 – 15 days (can vary from weeks to months) P.malariae infection can start after 28 days. Doctortvrao’s ‘e’ learning series Clinical Features ofMalaria : Clinical Features ofMalaria Clinical Manifestations are related to cycle of events in relation to RBC : Clinical Manifestations are related to cycle of events in relation to RBC How Malaria present Clinically : How Malaria present Clinically Stage 1 Chills for 15 mt to 1 hour Caused due to rupture from the host red cells escape into Blood Preset with nausea, vomitting,headache Stage 2 Fever may reach upto 400c may last for several hours starts invading newer red cells. Clinical Malaria : Clinical Malaria Stage 3 Patent starts sweating, concludes the episode Cycles are frequently Asynchronous Paroxysms occur every 48 – 72 hours In P.malariae pyrexia may lost for 8 hours or more and temperature my exceed 410c Doctortvrao’s ‘e’ learning series More commonly, the patient presents with a combination of the following symptoms : More commonly, the patient presents with a combination of the following symptoms Fever Chills Sweats Headaches Nausea and vomiting Body aches General malaise. Doctortvrao’s e learning Early symptoms : Early symptoms The common first symptoms – fever, headache, chills and vomiting – usually appear 10 to 15 days after a person is infected. If not treated promptly with effective medicines, malaria can cause severe illness and is often fatal. What are the characteristics of a malaria attack : What are the characteristics of a malaria attack Fever and shivering. The attack begins with fever, with the temperature rising as high as 40ºC and falling again over a period of several hours. A poor general condition, feeling unwell and having headaches like influenza. Diarrhea, nausea and vomiting often occur as well. Doctortvrao’s ‘e’ learning series Malaria the disease : Malaria the disease 9-14 day incubation period Fever, chills, headache, back and joint pain Gastrointestinal symptoms (nausea, vomiting, etc.) Clinical events : Clinical events The symptoms often associated with malaria are due to bursting red blood cells and clogged capillaries of major organs. Infection occurs when an infected anopheles mosquito feeds on an individual releasing sporozites into the blood stream. Mosquitos can carry more than one species and thus can infect peoples with more than one species Doctortvrao’s ‘e’ learning series Malaria stages of the disease : Malaria stages of the disease Malaria intensifies : Malaria intensifies Symptoms intensify Irregular high fever Anxiety, delirium and other mental problems Sweating, increased pulse rate, severe exhaustion Worsening GI symptoms Enlarged spleen and liver Broad clinical manifestations of Malaria : Broad clinical manifestations of Malaria Fever Sweating Anemia Splenomagaly (enlarged spleen) Irratability Coma, Retinal Hemorrages Algid Malaria ( a shocklike syndrome) Respiratory distress syndrome Periodicity can be clue in Diagnosis and species relation : Periodicity can be clue in Diagnosis and species relation Malaria tertiana: 48h between fevers (P. vivax and ovale) Malaria quartana: 72h between fevers (P. malariae) Malaria tropica: irregular high fever (P. falciparum) Malaria the disease : Malaria the disease Pathogenesis of Malaria : Pathogenesis of Malaria In highly endemic areas: high mortality among children due to severe anemia, children who survive beyond the first years show decreasing parasitemia and disease (this immunity is not sterile and depends on constant exposure) Doctortvrao’s ‘e’ learning series Cytokines & toxins : Cytokines & toxins Hatched=chill Black=rigor Clear=sweating Malaria produces a strong Th-1 type response Elevated serum levels of IFNg and TNFa Cytokines can induce (mimic) many of the symptoms and signs of malaria (shivering, headache, chills, spiking fever, sweating, vasodilation, hypoglycemia) Cerebral Malaria : Cerebral Malaria Malignant malaria can affect the brain and the rest of the central nervous system. It is characterized by changes in the level of consciousness, convulsions and paralysis. Cerebral Malaria : Cerebral Malaria Present with Hyperpyrexia Can lead to Coma Paralysis and other complications. Brain appears congested Pathogenesis of Cerebral malaria : Pathogenesis of Cerebral malaria High cytokine levels could be toxic on their own High levels of cytokine also enhance the second process thought to be responsible for cerebral malaria: sequestration of infected RBCs Sequestration & cytoadherence : Sequestration & cytoadherence Rosetting (adhesion of infected RBCs to other RBCs) and clumping (adhesion between infected cells) was first observed in in vitro culture Rosetting was also found in 50% of field isolates and correlated strongly with the severity of the observed disease Sequestration & cytoadherence : Sequestration & cytoadherence How do parasite proteins travel to the surface of the RBC? This is a considerable challenge as RBC lack functional secretory apparatus Why do patients fail to mount an effective immune response against antigens that are presented this prominently? Black water fever : Black water fever In malignant malaria a large number of the red blood corpuscles are destroyed. Hemoglobin from the blood corpuscles is excreted in the urine, which therefore is dark and almost the color of cola. How long Malaria infection can lost in Man : How long Malaria infection can lost in Man Without treatment P.falciparum will terminate in less than 1 year. But in P.vivax and P.ovale persist as hypnozoites after the parasites have disppeared from blood. Can prodce periodic relapses upto 5 years In P.malariae may last for 40 years ( Called as recrudescence X relapse ) Parasites survive in erythrocytes Liver ? Doctortvrao’s ‘e’ learning series Why Falciparum Infections are Dangerous : Why Falciparum Infections are Dangerous Can produce fatal complications, 1.Cerebral malaria 2.Malarial hyperpyrexia 3.Gastrointestinal disorders. 4.Algid malaria 5 Black water fever can lead to death Doctortvrao’s ‘e’ learning series Complication of P.malariae : Complication of P.malariae Can produce Nephrotic syndrome Affects mainly children of years age Pernicious MalariaCarries a High Mortality : Pernicious MalariaCarries a High Mortality On few occasions life threading complications can occur. Occurs in infections with P.falciparum Associated with Heavy parasitaztion Grouped into three types 1. Cerebral Malaria 2 Algid malaria 3 Black water fever Uncomplicated Malaria : Uncomplicated Malaria The classical (but rarely observed) malaria attack lasts 6-10 hours. It consists of: a cold stage (sensation of cold, shivering) a hot stage (fever, headaches, vomiting; seizures in young children) and finally a sweating stage (sweats, return to normal temperature, tiredness) Doctortvrao’s ‘e’ learning series Malaria A Major Health problem of Tropical countreis : Malaria A Major Health problem of Tropical countreis Pernicious Malaria : Pernicious Malaria Is a life threatening complication in acute falciparum malaria It is due to heavy parasitization Manifest with 1 Cerebral malaria – it presents with hyperpyrexia, coma and paralysis. Brain is congested 2 Algid malaria – presents with clammy skin leading to peripheral circulatory failure. Complication in Malaria : Complication in Malaria Pulmonary edema (fluid buildup in the lungs) or acute respiratory distress syndrome (ARDS), which may occur even after the parasite counts have decreased in response to treatment Abnormalities in blood coagulation and thrombocytopenia (decrease in blood platelets) Cardiovascular collapse and shock Black water Fever : Black water Fever It is a manifestation of infection with P.falciparum occuring in persons who have been previously infected and have had been inadequate dose of quinine It is characterized by intravascular hemolysis fever, and Haemoglobunuria Cardiovascular collapse and shock Abnormalities in blood coagulation and thrombocytopenia (decrease in blood platelets) Other Complications In Malaria : Other Complications In Malaria Acute kidney failure Hyperparasitemia, where more than 5% of the red blood cells are infected by malaria parasites Metabolic acidosis (excessive acidity in the blood and tissue fluids), often in association with hypoglycemia Immunity : Immunity Influenced by Genetics Age Health condition Pregnancy status Intensity of transmission in region Length of exposure Maintenance of exposure Immunity : Immunity Innate Red cell polymorphisms associated with some protection Hemoglobin S sickle cell trait or disease Hemoglobin C and hemoglobin E Thalessemia – a and ß Glucose – 6 – phosphate dehydrogenase deficiency (G6PD) Red cell membrane changes Absence of certain Duffy coat antigens improves resistance to P.v. Immunity : Immunity Acquired Transferred from mother to child 3-6 months protection Then children have increased susceptibility Increased susceptibility during early childhood Hyper- and holoendemic areas By age 5 attacks usually < frequent and severe Can have > parasite densities with fewer symptoms Meso- or hypoendemic areas Less transmission and repeated attacks May acquire partial immunity and be at higher risk for symptomatic disease as adults Immunity : Immunity Acquired No complete immunity Can be parasitemic without clinical disease Need long period of exposure for induction May need continued exposure for maintenance Immunity can be unstable Can wane as one spends time outside endemic area Can change with movement to area with different endemicity Decreases during pregnancy, risk improves with increasing gravidity Laboratory Diagnosis of Malaria : Laboratory Diagnosis of Malaria Diagnostic Toolsfor Human Infections with Malaria : Diagnostic Toolsfor Human Infections with Malaria Blood film examination Serology - IFA PCR Blood collected with sterile technique : Blood collected with sterile technique Making the smears : Making the smears Making of Thick smear : Making of Thick smear Thin and Thick smear : Thin and Thick smear Appearance of Thick and Thin Smears : Appearance of Thick and Thin Smears Microscopy : Microscopy Malaria parasites can be identified by examining under the microscope a drop of the patient's blood, spread out as a "blood smear" on a microscope slide. Prior to examination, the specimen is stained (most often with the Giemsa stain) to give to the parasites a distinctive appearance. This technique remains the gold standard for laboratory confirmation of malaria Doctortvrao’s ‘e’ learning series How parasites appear : How parasites appear QBC system has evolved as rapid and precise method in Diagnosis : QBC system has evolved as rapid and precise method in Diagnosis The QBC Malaria method is the simplest and most sensitive method for diagnosing the following diseases. Malaria Babesiosis Trypanosomiasis (Chagas disease, Sleeping Sickness) Filariasis (Elephantiasis, Loa-Loa) Relapsing Fever (Borreliosis) Doctortvrao’s ‘e’ learning series QBC system : QBC system Appearance of Malarial parasite in QBC system : Appearance of Malarial parasite in QBC system Antigen Detection Methods are Rapid and Precise : Antigen Detection Methods are Rapid and Precise Antigen Detection Various test kits are available to detect antigens derived from malaria parasites. Such immunologic ("immunochromatographic") tests most often use a dipstick or cassette format, and provide results in 2-15 minutes. These "Rapid Diagnostic Tests" (RDTs) offer a useful alternative to microscopy in situations where reliable microscopic diagnosis is not available. Malaria RDTs are currently used in some clinical settings Serology : Serology Serology detects antibodies against malaria parasites, using either indirect immunofluorescence (IFA) or enzyme-linked immunosorbent assay (ELISA). Serology does not detect current infection but rather measures past experience. Doctortvrao’s ‘e’ learning series Newer Diagnostic methods : Newer Diagnostic methods Molecular Diagnosis Parasite nucleic acids are detected using polymerase chain reaction (PCR). This technique is more accurate than microscopy. However, it is expensive, and requires a specialized laboratory (even though technical advances will likely result in field-operated PCR machines). Types of Serological Assays Malaria : Types of Serological Assays Malaria Antibody Detection Indirect Fluorescent Antibody Enzyme immunoassays Antigen Detection Immunochromatographic Antibody Detection : Antibody Detection Antibody Detection : Antibody Detection Indirect Fluorescent Antibody (IFA) : Indirect Fluorescent Antibody (IFA) Microscope slide Enzyme Immunoassay (EIA/ELISA) : Enzyme Immunoassay (EIA/ELISA) Slide 124: ELISA Antigen Detection : Antigen Detection Antigen Detection : Antigen Detection Antigen DetectionMalaria Immunochromatographic Dipstick : Antigen DetectionMalaria Immunochromatographic Dipstick Optimal Assay Control Plasmodium pan specific monoclonal antibody P. falciparum specific monoclonal antibody Malaria IFA Test : Malaria IFA Test Sensitivity = 98% Specificity = 99.5% Sulzer et al, Am J Trop Med Hyg 1969;18:199-205 Sulzer et al, Bull Wld Hlth Org 1971;45:375-379 Slide 129: P malaria Malaria IFA TestInitial detection of antibodies : Malaria IFA TestInitial detection of antibodies Parasitemia precedes antibody P. vivax 2-6 days P. falciparum and P. malariae 4-6 days If parasitemia is suppressed by treatment, may develop detectable antibody Malaria IFA TestDetermination of Infecting Species : Malaria IFA TestDetermination of Infecting Species Non-Immune Samples drawn 0-14 days post onset: Highest titer was to the infecting species in 81% Samples drawn 15-60 days post onset: Highest titer was to the infecting species in 96% Malaria IFA TestDetermination of Infecting Species : Malaria IFA TestDetermination of Infecting Species Is possible in non-immune individuals with primary infection. Is NOT possible in immune individuals because their antibody response reflects multiple infections with multiple species. Malaria IFA TestAntibody Persistence after Treatment : Malaria IFA TestAntibody Persistence after Treatment Non-Immunes (Vietnam Vets with Pv) 53% IFA negative at 6 mo. post-Rx 59% IFA negative at 12 mo. post-Rx Wilson et al, Am J Trop Med Hyg 1970;19:401-404 Malaria IFA TestAntibody Persistence after Treatment : Malaria IFA TestAntibody Persistence after Treatment Non-Immunes (Vietnam Vets with Pv) 53% IFA negative at 6 mo. post-Rx 59% IFA negative at 12 mo. post-Rx Wilson et al, Am J Trop Med Hyg 1970;19:401-404 Sensitivity of Tools forDiagnosis of Malarial Infection : Sensitivity of Tools forDiagnosis of Malarial Infection Most sensitive: Antibody detection 2. PCR 3. Blood film examination Diagnosis of Untreated Acute Malaria : Diagnosis of Untreated Acute Malaria Blood film examination PCR Diagnosis of Chronic Malaria : Diagnosis of Chronic Malaria Screen with serology If IFA positive: May do blood film examination May do PCR Doctortvrao’s ‘e’ learning series Diagnosis of Treated Recent Malaria : Diagnosis of Treated Recent Malaria Serology Blood film examination PCR Malaria Relapses : Malaria Relapses In P. vivax and P. ovale infections, patients having recovered from the first episode of illness may suffer several additional attacks ("relapses") after months or even years without symptoms. Relapses occur because P. vivax and P. ovale have dormant liver stage parasites ("hypnozoites") that may reactivate. Treatment to reduce the chance of such relapses is available and should follow treatment of the first attack. Treatment : Treatment Over view of Treatment options in Malaria : Over view of Treatment options in Malaria Most drugs used in treatment are active against the parasite forms in the blood (the form that causes disease) and include: Chloroquine Sulfadoxine-pyrimethamine (Fansidar®) Mefloquine (Lariam®) Atovaquone-proguanil (Malarone®) Quinine Doxycycline Artemisin derivatives (not licensed for use in the United States, but often found overseas) Slide 142: In endemic areas, the World Health Organization recommends that treatment be started within 24 hours after the first symptoms appear. Treatment of patients with uncomplicated malaria can be conducted on an ambulatory basis (without hospitalization) but patients with severe malaria should be hospitalized if possible. Doctortvrao’s ‘e’ learning series What is presumptive treatment? : What is presumptive treatment? Presumption - In an area with high transmission of malaria, it should be presumed that ALL cases of fever are due to malaria. Treatment - First loading dose of Chloroquine should be administered immediately after collecting the blood specimen, even without waiting for its report. If the fever is indeed malaria, this treatment alleviates symptoms early, may be well before the test result is available. If it is malaria, Chloroquine also prevents the spread of malaria by destroying the gametocytes of P. vivax (the more common malaria). If it is not malaria, nothing is lost, for Chloroquine at this dose is safe and has no adverse effects! Radical treatment : Radical treatment Radical treatment is administration of Primaquin to all confirmed cases of malaria. In P. vivax malaria, 2 weeks' therapy with Primaquin completely cures the infection in the host by its tissue schizonticidal activity and thereby prevents relapses. In P. falciparum malaria, a single dose of primaquine destroys the gametocytes, thereby prevents the spread of the infection into the mosquito. Use of Primaquin : Use of Primaquin Primaquine is active against the dormant parasite liver forms (hypnozoites) and prevents relapses. Primaquine should not be taken by pregnant women or by people who are deficient in G6PD (glucose-6-phosphate dehydrogenase). Patients should not take primaquine until a screening test has excluded G6PD deficiency. Doctortvrao’s ‘e’ learning series Drug Resistance : Drug Resistance Choroquine Resistance : Choroquine Resistance Chloroquine resistant P. falciparum (CRPF) first developed independently in 3 to 4 foci in Southeast Asia, Oceania , and South America in the late 1950's and early 1960's. Since then, Chloroquine resistance has spread to nearly all areas of the world where falciparum malaria is transmitted Chloroquine Resistance : Chloroquine Resistance Chloroquine resistant P. vivax (CRPV) malaria was first identified in 1989 among Australians living in or travelling to Papua New Guinea. CRPV has also now been identified in Southeast Asia, on the Indian subcontinent, and in South America. Vivax malaria, particularly from Oceania, also exhibits decreased susceptibility to primaquine. Testing Drug Resistance : Testing Drug Resistance There are 4 basic methods for testing malaria for drug resistance: in vivo tests, in vitro tests, molecular characterization, and animal models. Of these, only the first 3 are routinely done In vivo tests: In these tests, patients with clinical malaria are given a treatment dose of an antimalarials drug under observation and are monitored over time for either failure to clear parasites or for reappearance of parasites. Doctortvrao’s ‘e’ learning series In vitro Testing : In vitro Testing In vitro tests: In these tests, blood samples from malaria patients are obtained and the malaria parasites are exposed to different concentrations of antimalarials drugs in the laboratory. Some methods call for adaptation of parasites to culture first, while others put blood directly from patients into the test system. Molecular Methods : Molecular Methods Molecular characterization: For some drugs (Chloroquine, SP and similar drugs, atovaquone), molecular markers have been identified that confer resistance. Molecular techniques, such as polymerase chain reaction (PCR) or gene sequencing can identify these markers in blood taken from malaria-infected patien Slide 152: Resistance to Chloroquine - 1960 Slide 153: Resistance to Chloroquine - 1970 Slide 154: Resistance to Chloroquine - 1980 Slide 155: Resistance to Chloroquine - 2000 Slide 156: Intensification of Chloroquine Resistance in Africa Slide 157: Antimalarials Resistance - 1998 (excluding CQ) SP, Mefloquine, Halofantrine, Quinine SP Mefloquine SP, Mefloquine Slide 158: Reports of Chloroquine Resistance in P.vivax 1989 1990 1995 1995 1991 1995 World Malaria Day, April 25 : World Malaria Day, April 25 April 25 is World Malaria Day, which commemorates the date in 2000 when 44 African leaders committed to cutting malaria deaths in half by 2010. This year's World Malaria Day theme is "Counting Malaria Out." How does CDC contribute? CDC's malaria Web site offers telediagnosis and treatment strategies : CDC's malaria Web site offers telediagnosis and treatment strategies You can e-mail a digital image to the Centres for Disease Control and Prevention for telediagnosis, and if necessary download guidelines for treatment from its new malaria Web site, Tele Net Working : Tele Net Working Images of other suspected parasitic infections can be e-mailed to the CDC's Laboratory Identification of Parasites of Public Health Concern program (www.dpd.cdc.gov/dpdx). Doctortvrao’s ‘e’ learning series Development of Vaccines : Development of Vaccines Malaria vaccines in development include: pre-erythrocytic or liver-stage vaccines that aim to protect against the early stage of malaria infection; blood-stage vaccines that aim to reduce the severity of disease; and transmission-blocking vaccines that are intended to prevent mosquitoes that fed on an infected person from spreading malaria to new hosts. Future Ambitions : Future Ambitions The malaria vaccine community aims to license—by 2015—a first-generation vaccine that has 50 percent efficacy against severe disease and death, with protection lasting at least one year without the need for boosting. They also aim to license—by 2025—a second-generation malaria vaccine that has a protective efficacy of at least 80 percent against clinical disease and with protection lasting for many years without a booster. Why vaccines are Difficult : Why vaccines are Difficult No licensed vaccine against malaria currently exists The parasite has evolved a series of strategies that allow it to confuse, hide, and misdirect the human immune system. The parasite changes through several life stages even while in the human host, presenting a different subset of molecules for the immune system to combat at each stage. Simple protective Measures : Simple protective Measures There's no reason only poor people should get malaria': The moment Bill Gates released jar of mosquitoes at packed conference : There's no reason only poor people should get malaria': The moment Bill Gates released jar of mosquitoes at packed conference Bill and Melinda Gates Foundation that announced last year it was donating £115 million to help develop a vaccine for the deadly disease. : Bill and Melinda Gates Foundation that announced last year it was donating £115 million to help develop a vaccine for the deadly disease. Goal of Medical Humanity : Goal of Medical Humanity Created for Medical and Paramedical students in Developing World : Created for Medical and Paramedical students in Developing World Dr.T.V.Rao MD Email doctortvrao@gmail.com You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.
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In 2700 BC, several characteristic symptoms of what would later be named malaria were described in the Nei Ching, Hippocrates and Malaria : Hippocrates and Malaria Hippocrates, a physician born in ancient Greece, today regarded as the "Father of Medicine", was the first to describe the manifestations of the disease, and relate them to the time of year and to where the patients lived. Malaria : Malaria Name is derived from Italian Mal’ aria or bad air Malaria continues to be most important cause of fever and morbidity in the Tropical world Malaria has been eradicated from Europe, Most of North America, USA South America Korea and Japan, Slide 5: Malaria-endemic Areas 2000 Why it is important in Medicine : Why it is important in Medicine Malaria remains the world's most devastating human parasitic infection. Malaria affects over 40% of the world's population. WHO, estimates that there are 350 - 500 million cases of malaria worldwide, of which 270 - 400 million are Falciparum malaria, the most severe form of the disease. Malaria Kills more people than AIDS : Malaria Kills more people than AIDS Malaria kills in one year what AIDS kills in 15 years. For every death due to HIV/AIDS there are about 50 deaths due to malaria. To add to the problem is the increasing drug resistance to the established drug. History – Events on Malaria : History – Events on Malaria 1880 - Charles Louis Alphose Lavern discovered malarial parasite in wet mount 1883 - Methylene blue stain - Marchafava 1891 - Polychrome stain- Romanowsky 1898 - Roland Ross - Life cycle of parasite transmission, wins Nobel Prize in 1902 1948 - Site of Exoerythrocytic development in Liver by Shortt and Garnham Major Developments in 20th Century : Major Developments in 20th Century 1955 - WHO starts world wide malaria eradication programme using DDT 1970 – Mosquitos develop resistance to DDT Programme fails 1976 – Trager and Jensen in vitro cultivation of parasite Charles Louis Alphonse Laveran, : Charles Louis Alphonse Laveran, Charles Louis Alphonse Laveran, a French army surgeon stationed in Constantine, Algeria, was the first to notice parasites in the blood of a patient suffering from malaria. This occurred on the 6th of November 1880. For his discovery, Laveran was awarded the Nobel Prize in 1907. Doctortvrao’s ‘e’ learning series Ronald Ross : Ronald Ross In August 20th, 1897, Ronald Ross, a British officer in the Indian Medical Service, was the first to demonstrate that malaria parasites could be transmitted from infected patients to mosquitoes For his discovery, Ross was awarded the Nobel Prize in 1902. Doctortvrao’s ‘e’ learning series Nobel Prizes in Malaria : Nobel Prizes in Malaria The discovery of this parasite in mosquitoes earned the British scientist Ronald Ross the Nobel Prize in Physiology or Medicine in 1902. In 1907, Alphonse Lavern received the Nobel prize for his findings that the parasite was present in human blood. Chloroquine (Resochin) (1934, 1946) : Chloroquine (Resochin) (1934, 1946) Chloroquine was discovered by a German, Hans Andersag, in 1934 at Bayer I.G. Farbenindustrie A.G. laboratories in Eberfeld, Germany. He named his compound resochin. Through a series of lapses and confusion brought about during the war, chloroquine was finally recognized and established as an effective and safe antimalarial in 1946 by British and U.S. Doctortvrao’s ‘e’ learning series Malaria a vector borne Disease : Malaria a vector borne Disease Malaria is a vector-borne infectious disease caused by protozoan parasites. It is widespread in tropicl and subtropical regions, including parts of the Americas, Asia, and Africa. Female Anopheles Mosquitos transmit Malaria : Female Anopheles Mosquitos transmit Malaria Parasites Cause of Malaria : Parasites Cause of Malaria Malaria is caused by an infection by one of four single celled Plasmodia species, they are: falciparum, vivax, malariae, and ovale. The most dangerous of the four is.P.falciparum Newer species : Newer species A fifth species, Plasmodium knowlesi, causes malaria in macaques but can also infect humans. Doctortvrao’s ‘e’ learning series SPOROZOA : SPOROZOA SPOROZOA belong to phylum Apicomplexa – contains two classes 1 Haematozoea 2 Coccidea Belong to class Haematozoea occur in the blood of the vertebrate hosts contain two orders Haemosporidia (genus Plasmodium – Malaria ) Piroplasmidia (containing genus Babesia) Doctortvrao’s ‘e’ learning series Structure of Malarial parasite : Structure of Malarial parasite Falciparum most Dangerous : Falciparum most Dangerous Falciparum accounts for 90% of deaths due to malaria and vivax is the most widely spread species because it exists in both temperate and tropical climates (Encarta). The malaria life cycle is a complex system with both sexual and asexual aspects . Doctortvrao’s ‘e’ learning series A complex Life cycle : A complex Life cycle Human Cycle : Human Cycle 1 Pre erythrocytic schizogony 2 Erythrocytic Schizogony 3 Gametogony 4 Exoerythrocytic schizogony Doctortvrao’s ‘e’ learning series Events in Humans start with Bite of Mosquito : Events in Humans start with Bite of Mosquito Man – Intermediate host. Mosquito – Definitive host – Sporozoites are infective forms Present in the salivary gland of female anopheles mosquito After bite of infected mosquito sporozoites are introduced into blood circulation. Doctortvrao’s ‘e’ learning series Period of Pre erythrocytic cycle : Period of Pre erythrocytic cycle 1 P.vivax 8 days 2 P.falciparum – 6 days 3 P.malariae - 13 – 16 days, 4 P.ovale 9 days On maturation Liver cells ruputure Liberate Merozoites into blood stream Doctortvrao’s ‘e’ learning series Pre erythrocytic cycle : Pre erythrocytic cycle Sprozoites undergo developemtnal phase in the liver cell Sprozoites are elongated and spindle shaped become rounded inside the liver parenchyma Multiple nuclear divisions develop to Schozonts A Schizont contains 20,000 – 50,000 merozoites. Doctortvrao’s ‘e’ learning series Slide 28: Exo- erythrocytic (hepatic) cycle Malaria Life Cycle Life Cycle Schizogony Sporogony Exo-erythrocytic (tissue) phase : Exo-erythrocytic (tissue) phase P. malariae or P. falciparum sporozoites do not form hypnotizes, develop directly into pre-erythrocytic schizonts in the liver Pre-erythrocytic schizogeny takes 6-16 days post infection Schizonts rupture, releasing merozoites which invade red blood cells (RBC) in liver Affinity of Parasite to Erythrocytes : Affinity of Parasite to Erythrocytes P.vivax P.malariae Infectes only young or P.ovale Old Erythocytes P.falciparum Infects all age groups Also adhere to the endothelial lining of Blood vessesl Causes the obstruction, Thrombosis and Local Ischemias Erythrocyte cycle : Erythrocyte cycle Merozoites released invade red cells P.vivax infects young erythrocytes P.malariae Infects old erythrocytes P.falciparum infects RBC of all ages The Merozoites are pear shaped 1-5 microns in length The receptors for Merozoites are on red cells in the glycoprotein Doctortvrao’s ‘e’ learning series Erythrocytic Schizogony : Erythrocytic Schizogony Liberated Merozoites penetrate RBC Three stages occur 1 Trophozoites 2 Schizont 3 Merozoite Erythrocytic cycle : Erythrocytic cycle Ruptured red cells release Merozoites which attack new red cells Continue with Schizogony Repeated cycles will continue In P.falciparum - infected erythrocytes with Schizonts aggregate in the capillaries of brain and other internal organs Only ring forms are seen in the blood smears Trophozoites : Trophozoites After invasion grow and feed on hemoglobin Blue cytoplasm and red nucleus, Called as Signet ring appearance Hence called ring form Schizont : Schizont When the Trophozoite is fully developed becomes compact. Malarial pigments are scattered through the cytoplasm The Nucleus is large and lies at the periphery starts dividing. Becomes Schizont Doctortvrao’s ‘e’ learning series Plasmodium vivax : Plasmodium vivax Number of merozoites 12 to 24 arranged in grape like clusters RBC enlarged Schuffner’s dots present Yellowish brown fine granules Schizont 9-10 microns fills and enlarged Red cell Gametocytes – spherical or globular Size much larger than red cell Male 9 microns Female 10 – 11 microns Doctortvrao’s ‘e’ learning series Plasmodium falciparum : Plasmodium falciparum RBC is normal size Maurer’s dots 9 large red spots sometimes basophilic stippling Dark brown or blackish one or two solid blocks Gametocytes Crescentric, larger than a red cell 9 -10 microns, male and female 12- 14 microns Plasmodium malaria : Plasmodium malaria RBC Normal size Contain Ziemann’s stippling Contain dark brown coarse granules Schizont – 6 – 7 microns almost fills a normal sized red cell. Gametocytes Spherical or globular Size much larger than a red cell Plasmodium ovale : Plasmodium ovale Infected RBC slightly larger Contain Schuffner’s dots coarse granules Schizont 6.2 microns fills three quarters Merozoites 6 -12 fills three quarters Gametocytes Spherical or globular, much larger than a red cell Doctortvrao’s ‘e’ learning series Exo-erythrocytic (tissue) phase : Exo-erythrocytic (tissue) phase P. malariae or P. falciparum sporozoites do not form hypnozites, develop directly into pre-erythrocytic schizonts in the liver Pre-erythrocytic schizogeny takes 6-16 days post infection Schizonts rupture, releasing merozoites which invade red blood cells (RBC) in liver Exo Erythrocytic Schizogony : Exo Erythrocytic Schizogony Some Sprozoites do not undergo sporogony in the first instance But go into resting stage called as Hypnozoites,( hibernation ) Within 2 years reactivate to form Schizonts release Merozoites and attack red cell and produce relapses Absent in P falciparum Doctortvrao’s ‘e’ learning series Gametogony : Gametogony Merozoites differentiate into Male and female gametocytes Macrogametocytes also called female gametocytes Microgametocyte also called as male gametocytes They develop in the red cells Found in the peripheral blood smears Microgametocyte of all species are similar in size Macro gametocytes are larger in size. Mosquito cycleA definitive Host – Mosquito : Mosquito cycleA definitive Host – Mosquito Mosquito cycleSexual cycle : Mosquito cycleSexual cycle Sexual cycle will be initiated in the Humans by the formation of Gametocytes Develop further in the female Anopheles Mosquito Only mature sexual forms are capable of further development in Mosquito In midgut one Microgametocyte develops into 4-8 thread like filamentous structures named Micro gametes From one macrogametocyte only one macrogamete is formed Events in Mosquitos : Events in Mosquitos Fertilization occurs when a Microgametocyte penetrate into Macrogametocyte Fertilized macrogametocyte is known as ZYGOTE ZYGOTE matures into OOKINETE OOKINETE to OOCYST Formation of Sporozoites in Mosquitos. : Formation of Sporozoites in Mosquitos. OOCYST matures with large number of Sporozoites ( A few hundred to thousands.) OOCYST ruptures and release SPOROZOITES in the body cavity of Mosquito There is a specific predilection for salivary glands Now capable to transmit the infection to new Host Doctortvrao’s ‘e’ learning series Pathology and Pathogenesis : Pathology and Pathogenesis Sporozoites result from sexaul and sporogenic cycle of development in mosquitoes and injected into human blood serum. Events start with bite of Infected Anopheles Mosquitoes Sporoozoites enter liver, in 1 hour infect the parenchymal cell. Pathology and Pathogenesis : Pathology and Pathogenesis Sporozoites result from sexaul and sporogenic cycle of development in mosquitoes and injected into human blood serum. Events start with bite of Infected Anopheles Mosquitoes Sporoozoites enter liver, in 1 hour infect the parenchymal cell. Pathogenesis in Pre Erythrocyte cycle : Pathogenesis in Pre Erythrocyte cycle Numerous asexual progeny – Merozoites ruputure and leave from liver cells Enter the Blood and invade Erythrocytes Erythrocytic cycle starts – Multiply in species specific fashion Broods of Merozoites appearing at 48 hour interval in P.ovale, P.vivax , P.falciparum P.malariae appear in 72 hour cycles, Chooses to enter the RBC : Chooses to enter the RBC Specific for each species They pit on red cells By endocytosis enters the RBC Becomes a Trophozoites Schizont : Schizont When the Trophozoite is fully developed becomes compact. Malarial pigments are scattered through the cytoplasm The Nucleus is large and lies at the periphery starts dividing. Becomes Schizont Doctortvrao’s ‘e’ learning series Cycles differs in Different species : Cycles differs in Different species Cycle repeats every 48 hours in 1 P.falciparum 2 P.ovale 3 P.vivax Repeats every 72 hours In P.malariae Doctortvrao’s ‘e’ learning series Incubation period varies according to species : Incubation period varies according to species Which includes Exo eythrocytic cycle time and one or two erythocytic cycles, P.vivax and P.falciparum 10 – 15 days (can vary from weeks to months) P.malariae infection can start after 28 days. Doctortvrao’s ‘e’ learning series Clinical Features ofMalaria : Clinical Features ofMalaria Clinical Manifestations are related to cycle of events in relation to RBC : Clinical Manifestations are related to cycle of events in relation to RBC How Malaria present Clinically : How Malaria present Clinically Stage 1 Chills for 15 mt to 1 hour Caused due to rupture from the host red cells escape into Blood Preset with nausea, vomitting,headache Stage 2 Fever may reach upto 400c may last for several hours starts invading newer red cells. Clinical Malaria : Clinical Malaria Stage 3 Patent starts sweating, concludes the episode Cycles are frequently Asynchronous Paroxysms occur every 48 – 72 hours In P.malariae pyrexia may lost for 8 hours or more and temperature my exceed 410c Doctortvrao’s ‘e’ learning series More commonly, the patient presents with a combination of the following symptoms : More commonly, the patient presents with a combination of the following symptoms Fever Chills Sweats Headaches Nausea and vomiting Body aches General malaise. Doctortvrao’s e learning Early symptoms : Early symptoms The common first symptoms – fever, headache, chills and vomiting – usually appear 10 to 15 days after a person is infected. If not treated promptly with effective medicines, malaria can cause severe illness and is often fatal. What are the characteristics of a malaria attack : What are the characteristics of a malaria attack Fever and shivering. The attack begins with fever, with the temperature rising as high as 40ºC and falling again over a period of several hours. A poor general condition, feeling unwell and having headaches like influenza. Diarrhea, nausea and vomiting often occur as well. Doctortvrao’s ‘e’ learning series Malaria the disease : Malaria the disease 9-14 day incubation period Fever, chills, headache, back and joint pain Gastrointestinal symptoms (nausea, vomiting, etc.) Clinical events : Clinical events The symptoms often associated with malaria are due to bursting red blood cells and clogged capillaries of major organs. Infection occurs when an infected anopheles mosquito feeds on an individual releasing sporozites into the blood stream. Mosquitos can carry more than one species and thus can infect peoples with more than one species Doctortvrao’s ‘e’ learning series Malaria stages of the disease : Malaria stages of the disease Malaria intensifies : Malaria intensifies Symptoms intensify Irregular high fever Anxiety, delirium and other mental problems Sweating, increased pulse rate, severe exhaustion Worsening GI symptoms Enlarged spleen and liver Broad clinical manifestations of Malaria : Broad clinical manifestations of Malaria Fever Sweating Anemia Splenomagaly (enlarged spleen) Irratability Coma, Retinal Hemorrages Algid Malaria ( a shocklike syndrome) Respiratory distress syndrome Periodicity can be clue in Diagnosis and species relation : Periodicity can be clue in Diagnosis and species relation Malaria tertiana: 48h between fevers (P. vivax and ovale) Malaria quartana: 72h between fevers (P. malariae) Malaria tropica: irregular high fever (P. falciparum) Malaria the disease : Malaria the disease Pathogenesis of Malaria : Pathogenesis of Malaria In highly endemic areas: high mortality among children due to severe anemia, children who survive beyond the first years show decreasing parasitemia and disease (this immunity is not sterile and depends on constant exposure) Doctortvrao’s ‘e’ learning series Cytokines & toxins : Cytokines & toxins Hatched=chill Black=rigor Clear=sweating Malaria produces a strong Th-1 type response Elevated serum levels of IFNg and TNFa Cytokines can induce (mimic) many of the symptoms and signs of malaria (shivering, headache, chills, spiking fever, sweating, vasodilation, hypoglycemia) Cerebral Malaria : Cerebral Malaria Malignant malaria can affect the brain and the rest of the central nervous system. It is characterized by changes in the level of consciousness, convulsions and paralysis. Cerebral Malaria : Cerebral Malaria Present with Hyperpyrexia Can lead to Coma Paralysis and other complications. Brain appears congested Pathogenesis of Cerebral malaria : Pathogenesis of Cerebral malaria High cytokine levels could be toxic on their own High levels of cytokine also enhance the second process thought to be responsible for cerebral malaria: sequestration of infected RBCs Sequestration & cytoadherence : Sequestration & cytoadherence Rosetting (adhesion of infected RBCs to other RBCs) and clumping (adhesion between infected cells) was first observed in in vitro culture Rosetting was also found in 50% of field isolates and correlated strongly with the severity of the observed disease Sequestration & cytoadherence : Sequestration & cytoadherence How do parasite proteins travel to the surface of the RBC? This is a considerable challenge as RBC lack functional secretory apparatus Why do patients fail to mount an effective immune response against antigens that are presented this prominently? Black water fever : Black water fever In malignant malaria a large number of the red blood corpuscles are destroyed. Hemoglobin from the blood corpuscles is excreted in the urine, which therefore is dark and almost the color of cola. How long Malaria infection can lost in Man : How long Malaria infection can lost in Man Without treatment P.falciparum will terminate in less than 1 year. But in P.vivax and P.ovale persist as hypnozoites after the parasites have disppeared from blood. Can prodce periodic relapses upto 5 years In P.malariae may last for 40 years ( Called as recrudescence X relapse ) Parasites survive in erythrocytes Liver ? Doctortvrao’s ‘e’ learning series Why Falciparum Infections are Dangerous : Why Falciparum Infections are Dangerous Can produce fatal complications, 1.Cerebral malaria 2.Malarial hyperpyrexia 3.Gastrointestinal disorders. 4.Algid malaria 5 Black water fever can lead to death Doctortvrao’s ‘e’ learning series Complication of P.malariae : Complication of P.malariae Can produce Nephrotic syndrome Affects mainly children of years age Pernicious MalariaCarries a High Mortality : Pernicious MalariaCarries a High Mortality On few occasions life threading complications can occur. Occurs in infections with P.falciparum Associated with Heavy parasitaztion Grouped into three types 1. Cerebral Malaria 2 Algid malaria 3 Black water fever Uncomplicated Malaria : Uncomplicated Malaria The classical (but rarely observed) malaria attack lasts 6-10 hours. It consists of: a cold stage (sensation of cold, shivering) a hot stage (fever, headaches, vomiting; seizures in young children) and finally a sweating stage (sweats, return to normal temperature, tiredness) Doctortvrao’s ‘e’ learning series Malaria A Major Health problem of Tropical countreis : Malaria A Major Health problem of Tropical countreis Pernicious Malaria : Pernicious Malaria Is a life threatening complication in acute falciparum malaria It is due to heavy parasitization Manifest with 1 Cerebral malaria – it presents with hyperpyrexia, coma and paralysis. Brain is congested 2 Algid malaria – presents with clammy skin leading to peripheral circulatory failure. Complication in Malaria : Complication in Malaria Pulmonary edema (fluid buildup in the lungs) or acute respiratory distress syndrome (ARDS), which may occur even after the parasite counts have decreased in response to treatment Abnormalities in blood coagulation and thrombocytopenia (decrease in blood platelets) Cardiovascular collapse and shock Black water Fever : Black water Fever It is a manifestation of infection with P.falciparum occuring in persons who have been previously infected and have had been inadequate dose of quinine It is characterized by intravascular hemolysis fever, and Haemoglobunuria Cardiovascular collapse and shock Abnormalities in blood coagulation and thrombocytopenia (decrease in blood platelets) Other Complications In Malaria : Other Complications In Malaria Acute kidney failure Hyperparasitemia, where more than 5% of the red blood cells are infected by malaria parasites Metabolic acidosis (excessive acidity in the blood and tissue fluids), often in association with hypoglycemia Immunity : Immunity Influenced by Genetics Age Health condition Pregnancy status Intensity of transmission in region Length of exposure Maintenance of exposure Immunity : Immunity Innate Red cell polymorphisms associated with some protection Hemoglobin S sickle cell trait or disease Hemoglobin C and hemoglobin E Thalessemia – a and ß Glucose – 6 – phosphate dehydrogenase deficiency (G6PD) Red cell membrane changes Absence of certain Duffy coat antigens improves resistance to P.v. Immunity : Immunity Acquired Transferred from mother to child 3-6 months protection Then children have increased susceptibility Increased susceptibility during early childhood Hyper- and holoendemic areas By age 5 attacks usually < frequent and severe Can have > parasite densities with fewer symptoms Meso- or hypoendemic areas Less transmission and repeated attacks May acquire partial immunity and be at higher risk for symptomatic disease as adults Immunity : Immunity Acquired No complete immunity Can be parasitemic without clinical disease Need long period of exposure for induction May need continued exposure for maintenance Immunity can be unstable Can wane as one spends time outside endemic area Can change with movement to area with different endemicity Decreases during pregnancy, risk improves with increasing gravidity Laboratory Diagnosis of Malaria : Laboratory Diagnosis of Malaria Diagnostic Toolsfor Human Infections with Malaria : Diagnostic Toolsfor Human Infections with Malaria Blood film examination Serology - IFA PCR Blood collected with sterile technique : Blood collected with sterile technique Making the smears : Making the smears Making of Thick smear : Making of Thick smear Thin and Thick smear : Thin and Thick smear Appearance of Thick and Thin Smears : Appearance of Thick and Thin Smears Microscopy : Microscopy Malaria parasites can be identified by examining under the microscope a drop of the patient's blood, spread out as a "blood smear" on a microscope slide. Prior to examination, the specimen is stained (most often with the Giemsa stain) to give to the parasites a distinctive appearance. This technique remains the gold standard for laboratory confirmation of malaria Doctortvrao’s ‘e’ learning series How parasites appear : How parasites appear QBC system has evolved as rapid and precise method in Diagnosis : QBC system has evolved as rapid and precise method in Diagnosis The QBC Malaria method is the simplest and most sensitive method for diagnosing the following diseases. Malaria Babesiosis Trypanosomiasis (Chagas disease, Sleeping Sickness) Filariasis (Elephantiasis, Loa-Loa) Relapsing Fever (Borreliosis) Doctortvrao’s ‘e’ learning series QBC system : QBC system Appearance of Malarial parasite in QBC system : Appearance of Malarial parasite in QBC system Antigen Detection Methods are Rapid and Precise : Antigen Detection Methods are Rapid and Precise Antigen Detection Various test kits are available to detect antigens derived from malaria parasites. Such immunologic ("immunochromatographic") tests most often use a dipstick or cassette format, and provide results in 2-15 minutes. These "Rapid Diagnostic Tests" (RDTs) offer a useful alternative to microscopy in situations where reliable microscopic diagnosis is not available. Malaria RDTs are currently used in some clinical settings Serology : Serology Serology detects antibodies against malaria parasites, using either indirect immunofluorescence (IFA) or enzyme-linked immunosorbent assay (ELISA). Serology does not detect current infection but rather measures past experience. Doctortvrao’s ‘e’ learning series Newer Diagnostic methods : Newer Diagnostic methods Molecular Diagnosis Parasite nucleic acids are detected using polymerase chain reaction (PCR). This technique is more accurate than microscopy. However, it is expensive, and requires a specialized laboratory (even though technical advances will likely result in field-operated PCR machines). Types of Serological Assays Malaria : Types of Serological Assays Malaria Antibody Detection Indirect Fluorescent Antibody Enzyme immunoassays Antigen Detection Immunochromatographic Antibody Detection : Antibody Detection Antibody Detection : Antibody Detection Indirect Fluorescent Antibody (IFA) : Indirect Fluorescent Antibody (IFA) Microscope slide Enzyme Immunoassay (EIA/ELISA) : Enzyme Immunoassay (EIA/ELISA) Slide 124: ELISA Antigen Detection : Antigen Detection Antigen Detection : Antigen Detection Antigen DetectionMalaria Immunochromatographic Dipstick : Antigen DetectionMalaria Immunochromatographic Dipstick Optimal Assay Control Plasmodium pan specific monoclonal antibody P. falciparum specific monoclonal antibody Malaria IFA Test : Malaria IFA Test Sensitivity = 98% Specificity = 99.5% Sulzer et al, Am J Trop Med Hyg 1969;18:199-205 Sulzer et al, Bull Wld Hlth Org 1971;45:375-379 Slide 129: P malaria Malaria IFA TestInitial detection of antibodies : Malaria IFA TestInitial detection of antibodies Parasitemia precedes antibody P. vivax 2-6 days P. falciparum and P. malariae 4-6 days If parasitemia is suppressed by treatment, may develop detectable antibody Malaria IFA TestDetermination of Infecting Species : Malaria IFA TestDetermination of Infecting Species Non-Immune Samples drawn 0-14 days post onset: Highest titer was to the infecting species in 81% Samples drawn 15-60 days post onset: Highest titer was to the infecting species in 96% Malaria IFA TestDetermination of Infecting Species : Malaria IFA TestDetermination of Infecting Species Is possible in non-immune individuals with primary infection. Is NOT possible in immune individuals because their antibody response reflects multiple infections with multiple species. Malaria IFA TestAntibody Persistence after Treatment : Malaria IFA TestAntibody Persistence after Treatment Non-Immunes (Vietnam Vets with Pv) 53% IFA negative at 6 mo. post-Rx 59% IFA negative at 12 mo. post-Rx Wilson et al, Am J Trop Med Hyg 1970;19:401-404 Malaria IFA TestAntibody Persistence after Treatment : Malaria IFA TestAntibody Persistence after Treatment Non-Immunes (Vietnam Vets with Pv) 53% IFA negative at 6 mo. post-Rx 59% IFA negative at 12 mo. post-Rx Wilson et al, Am J Trop Med Hyg 1970;19:401-404 Sensitivity of Tools forDiagnosis of Malarial Infection : Sensitivity of Tools forDiagnosis of Malarial Infection Most sensitive: Antibody detection 2. PCR 3. Blood film examination Diagnosis of Untreated Acute Malaria : Diagnosis of Untreated Acute Malaria Blood film examination PCR Diagnosis of Chronic Malaria : Diagnosis of Chronic Malaria Screen with serology If IFA positive: May do blood film examination May do PCR Doctortvrao’s ‘e’ learning series Diagnosis of Treated Recent Malaria : Diagnosis of Treated Recent Malaria Serology Blood film examination PCR Malaria Relapses : Malaria Relapses In P. vivax and P. ovale infections, patients having recovered from the first episode of illness may suffer several additional attacks ("relapses") after months or even years without symptoms. Relapses occur because P. vivax and P. ovale have dormant liver stage parasites ("hypnozoites") that may reactivate. Treatment to reduce the chance of such relapses is available and should follow treatment of the first attack. Treatment : Treatment Over view of Treatment options in Malaria : Over view of Treatment options in Malaria Most drugs used in treatment are active against the parasite forms in the blood (the form that causes disease) and include: Chloroquine Sulfadoxine-pyrimethamine (Fansidar®) Mefloquine (Lariam®) Atovaquone-proguanil (Malarone®) Quinine Doxycycline Artemisin derivatives (not licensed for use in the United States, but often found overseas) Slide 142: In endemic areas, the World Health Organization recommends that treatment be started within 24 hours after the first symptoms appear. Treatment of patients with uncomplicated malaria can be conducted on an ambulatory basis (without hospitalization) but patients with severe malaria should be hospitalized if possible. Doctortvrao’s ‘e’ learning series What is presumptive treatment? : What is presumptive treatment? Presumption - In an area with high transmission of malaria, it should be presumed that ALL cases of fever are due to malaria. Treatment - First loading dose of Chloroquine should be administered immediately after collecting the blood specimen, even without waiting for its report. If the fever is indeed malaria, this treatment alleviates symptoms early, may be well before the test result is available. If it is malaria, Chloroquine also prevents the spread of malaria by destroying the gametocytes of P. vivax (the more common malaria). If it is not malaria, nothing is lost, for Chloroquine at this dose is safe and has no adverse effects! Radical treatment : Radical treatment Radical treatment is administration of Primaquin to all confirmed cases of malaria. In P. vivax malaria, 2 weeks' therapy with Primaquin completely cures the infection in the host by its tissue schizonticidal activity and thereby prevents relapses. In P. falciparum malaria, a single dose of primaquine destroys the gametocytes, thereby prevents the spread of the infection into the mosquito. Use of Primaquin : Use of Primaquin Primaquine is active against the dormant parasite liver forms (hypnozoites) and prevents relapses. Primaquine should not be taken by pregnant women or by people who are deficient in G6PD (glucose-6-phosphate dehydrogenase). Patients should not take primaquine until a screening test has excluded G6PD deficiency. Doctortvrao’s ‘e’ learning series Drug Resistance : Drug Resistance Choroquine Resistance : Choroquine Resistance Chloroquine resistant P. falciparum (CRPF) first developed independently in 3 to 4 foci in Southeast Asia, Oceania , and South America in the late 1950's and early 1960's. Since then, Chloroquine resistance has spread to nearly all areas of the world where falciparum malaria is transmitted Chloroquine Resistance : Chloroquine Resistance Chloroquine resistant P. vivax (CRPV) malaria was first identified in 1989 among Australians living in or travelling to Papua New Guinea. CRPV has also now been identified in Southeast Asia, on the Indian subcontinent, and in South America. Vivax malaria, particularly from Oceania, also exhibits decreased susceptibility to primaquine. Testing Drug Resistance : Testing Drug Resistance There are 4 basic methods for testing malaria for drug resistance: in vivo tests, in vitro tests, molecular characterization, and animal models. Of these, only the first 3 are routinely done In vivo tests: In these tests, patients with clinical malaria are given a treatment dose of an antimalarials drug under observation and are monitored over time for either failure to clear parasites or for reappearance of parasites. Doctortvrao’s ‘e’ learning series In vitro Testing : In vitro Testing In vitro tests: In these tests, blood samples from malaria patients are obtained and the malaria parasites are exposed to different concentrations of antimalarials drugs in the laboratory. Some methods call for adaptation of parasites to culture first, while others put blood directly from patients into the test system. Molecular Methods : Molecular Methods Molecular characterization: For some drugs (Chloroquine, SP and similar drugs, atovaquone), molecular markers have been identified that confer resistance. Molecular techniques, such as polymerase chain reaction (PCR) or gene sequencing can identify these markers in blood taken from malaria-infected patien Slide 152: Resistance to Chloroquine - 1960 Slide 153: Resistance to Chloroquine - 1970 Slide 154: Resistance to Chloroquine - 1980 Slide 155: Resistance to Chloroquine - 2000 Slide 156: Intensification of Chloroquine Resistance in Africa Slide 157: Antimalarials Resistance - 1998 (excluding CQ) SP, Mefloquine, Halofantrine, Quinine SP Mefloquine SP, Mefloquine Slide 158: Reports of Chloroquine Resistance in P.vivax 1989 1990 1995 1995 1991 1995 World Malaria Day, April 25 : World Malaria Day, April 25 April 25 is World Malaria Day, which commemorates the date in 2000 when 44 African leaders committed to cutting malaria deaths in half by 2010. This year's World Malaria Day theme is "Counting Malaria Out." How does CDC contribute? CDC's malaria Web site offers telediagnosis and treatment strategies : CDC's malaria Web site offers telediagnosis and treatment strategies You can e-mail a digital image to the Centres for Disease Control and Prevention for telediagnosis, and if necessary download guidelines for treatment from its new malaria Web site, Tele Net Working : Tele Net Working Images of other suspected parasitic infections can be e-mailed to the CDC's Laboratory Identification of Parasites of Public Health Concern program (www.dpd.cdc.gov/dpdx). Doctortvrao’s ‘e’ learning series Development of Vaccines : Development of Vaccines Malaria vaccines in development include: pre-erythrocytic or liver-stage vaccines that aim to protect against the early stage of malaria infection; blood-stage vaccines that aim to reduce the severity of disease; and transmission-blocking vaccines that are intended to prevent mosquitoes that fed on an infected person from spreading malaria to new hosts. Future Ambitions : Future Ambitions The malaria vaccine community aims to license—by 2015—a first-generation vaccine that has 50 percent efficacy against severe disease and death, with protection lasting at least one year without the need for boosting. They also aim to license—by 2025—a second-generation malaria vaccine that has a protective efficacy of at least 80 percent against clinical disease and with protection lasting for many years without a booster. Why vaccines are Difficult : Why vaccines are Difficult No licensed vaccine against malaria currently exists The parasite has evolved a series of strategies that allow it to confuse, hide, and misdirect the human immune system. The parasite changes through several life stages even while in the human host, presenting a different subset of molecules for the immune system to combat at each stage. Simple protective Measures : Simple protective Measures There's no reason only poor people should get malaria': The moment Bill Gates released jar of mosquitoes at packed conference : There's no reason only poor people should get malaria': The moment Bill Gates released jar of mosquitoes at packed conference Bill and Melinda Gates Foundation that announced last year it was donating £115 million to help develop a vaccine for the deadly disease. : Bill and Melinda Gates Foundation that announced last year it was donating £115 million to help develop a vaccine for the deadly disease. Goal of Medical Humanity : Goal of Medical Humanity Created for Medical and Paramedical students in Developing World : Created for Medical and Paramedical students in Developing World Dr.T.V.Rao MD Email doctortvrao@gmail.com