World Malaria Day


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World Malaria Day is celebrated to bring in awareness on the Universal importance of the Health problem killing millions in the world.

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  • The life cycle of all species that infect humans is basically the same. There is an exogenous asexual phase in the mosquito called sporogony during which the parasite multiplies. There is also an endogenous asexual phase that takes place in the vertebrate or human host that is called schizogeny. This phase includes the parasite development that takes place in the red blood cell, called the erythrocytic cycle and the phase tthat takes place in the parencymal cells in the liver, called the exo-erythrocytic phase. The exo-erthrocytic phase is also called the tissue phase. The schizogeny that takes place here can occur without delay during the primary infection or can be delayed in the case of relapses of malaria. I will focus on the development of the parasite in the human host.
  • Eight of the 8-kDa antigens were chemically synthesized and tested with a panel of defined sera in a FAST-ELISA. All sera were tested in triplicate against each synthetic protein. This plate shows the substrate development for one protein. For evaluation, the mean absorbance value for each serum was divided by the mean absorbance value for the positive reference serum to give a relative absorbance unit.
  • World Malaria Day

    1. 1. WORLD MALARIA DAY (25 th April) an update Dr.T.V.Rao MD
    2. 2. World Malaria Day - April 25 <ul><li>Malaria remains a killer disease with nearly 1 million people losing their lives every year. Eighty five per cent of deaths are children under 5 years of age. </li></ul><ul><li>Most malaria cases occur in Africa but it nevertheless remains a global problem also affecting countries in large parts of Asia and Latin America. </li></ul>
    3. 3. Importance of World Malaria Day <ul><li>It was first celebrated in 2008 following a resolution of the World Health Assembly in 2007. It aims to build greater awareness and understanding of malaria, its prevention, treatment, and control. </li></ul><ul><li>Malaria can cause severe illness and is often fatal but it is curable when diagnosed and treated promptly with effective medicines. Based on the World Health Organization data as of 2009, there are about 3.3 billion people who are at risk of malaria which leads to about 250 million malaria cases and a mortality of nearly one million people. </li></ul><ul><li>  </li></ul>
    4. 4. Malaria – Early History <ul><li>The symptoms of malaria were described in ancient Chinese medical writings. In 2700 BC, several characteristic symptoms of what would later be named malaria were described in the Nei Ching , </li></ul>
    5. 5. Hippocrates and Malaria <ul><li>Hippocrates, a physician born in ancient Greece, today regarded as the &quot;Father of Medicine&quot;, was the first to describe the manifestations of the disease, and relate them to the time of year and to where the patients lived. </li></ul>
    6. 6. Malaria <ul><li>Name is derived from Italian </li></ul><ul><li>Mal’ aria or bad air </li></ul><ul><li>Malaria continues to be most important cause of fever and morbidity in the Tropical world </li></ul><ul><li>Malaria has been eradicated from Europe, Most of North America, USA South America Korea and Japan, </li></ul>
    7. 7. Malaria-endemic Areas 2000
    9. 9. Why it is important in Medicine <ul><li>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. </li></ul>
    10. 10. Malaria Kills more people than AIDS <ul><li>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. </li></ul>
    11. 11. History – Events on Malaria <ul><li>1880 - Charles Louis Alphose Lavern discovered malarial parasite in wet mount </li></ul><ul><li>1883 - Methylene blue stain - Marchafava </li></ul><ul><li>1891 - Polychrome stain- Romanowsky </li></ul><ul><li>1898 - Roland Ross - Life cycle of parasite transmission, wins Nobel Prize in 1902 </li></ul><ul><li>1948 - Site of Exoerythrocytic development in Liver by Shortt and Garnham </li></ul>
    12. 12. Major Developments in 20 th Century <ul><li>1955 - WHO starts world wide malaria eradication programme using DDT </li></ul><ul><li>1970 – Mosquitos develop resistance to DDT Programme fails </li></ul><ul><li>1976 – Trager and Jensen in vitro cultivation of parasite </li></ul><ul><li>1948 - Site of E1948 - Site of Exoerythrocytic dev in Liver by Shortt and Garnham </li></ul><ul><li>xoerythrocytic dev in Liver by Shortt and Garnham </li></ul>
    13. 13. Charles Louis Alphonse Laveran , <ul><li>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. </li></ul>
    14. 14. Ronald Ross <ul><li>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. </li></ul><ul><li>Doctortvrao’s ‘e’ learning series </li></ul>
    15. 15. Nobel Prizes in Malaria <ul><li>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. </li></ul>
    16. 16. Chloroquine (Resochin) (1934, 1946) <ul><li>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. </li></ul><ul><li>Doctortvrao’s ‘e’ learning series </li></ul>
    17. 17. Malaria a vector borne Disease <ul><li>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. </li></ul>
    18. 18. Female Anopheles Mosquitos transmit Malaria
    19. 19. Parasites Cause of Malaria <ul><li>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 </li></ul>
    20. 20. Newer species of Mosquito <ul><li>A fifth species, Plasmodium knowlesi , causes malaria in macaques but can also infect humans. </li></ul><ul><li>Doctortvrao’s ‘e’ learning series </li></ul>
    21. 21. SPOROZOA <ul><li>SPOROZOA belong to phylum Apicomplexa – contains two classes </li></ul><ul><li>1 Haematozoea </li></ul><ul><li>2 Coccidea </li></ul><ul><li>Belong to class Haematozoea occur in the blood of the vertebrate hosts </li></ul><ul><li>contain two orders Haemosporidia (genus Plasmodium – Malaria ) </li></ul><ul><li>Piroplasmidia (containing genus Babesia ) </li></ul><ul><li>Doctortvrao’s ‘e’ learning series </li></ul>
    22. 22. Structure of Malarial parasite
    23. 24. Falciparum most Dangerous <ul><li>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 . </li></ul><ul><li>Doctortvrao’s ‘e’ learning series </li></ul>
    24. 25. A complex Life cycle
    25. 27. Human Cycle <ul><li>1 Pre erythrocytic schizogony </li></ul><ul><li>2 Erythrocytic Schizogony </li></ul><ul><li>3 Gametogony </li></ul><ul><li>4 Exoerythrocytic schizogony </li></ul><ul><li>Doctortvrao’s ‘e’ learning series </li></ul>
    26. 28. Events in Humans start with Bite of Mosquito <ul><li>Man – Intermediate host. </li></ul><ul><li>Mosquito – Definitive host </li></ul><ul><li>– Sporozoites are infective forms </li></ul><ul><li>Present in the salivary gland of female anopheles mosquito </li></ul><ul><li>After bite of infected mosquito sporozoites are introduced into blood circulation. </li></ul><ul><li>Doctortvrao’s ‘e’ learning series </li></ul>
    27. 29. Period of Pre erythrocytic cycle <ul><li>1 P.vivax 8 days </li></ul><ul><li>2 P.falciparum – 6 days </li></ul><ul><li>3 P.malariae - 13 – 16 days, </li></ul><ul><li>4 P.ovale 9 days </li></ul><ul><li>On maturation Liver cells ruputure </li></ul><ul><li>Liberate Merozoites into blood stream </li></ul><ul><li>Doctortvrao’s ‘e’ learning series </li></ul>
    28. 30. Pre erythrocytic cycle <ul><li>Sprozoites undergo developemtnal phase in the liver cell </li></ul><ul><li>Sprozoites are elongated and spindle shaped become rounded inside the liver parenchyma </li></ul><ul><li>Multiple nuclear divisions develop to Schozonts </li></ul><ul><li>A Schizont contains 20,000 – 50,000 merozoites. </li></ul><ul><li>Doctortvrao’s ‘e’ learning series </li></ul>
    29. 31. Exo- erythrocytic (hepatic) cycle Malaria Life Cycle Life Cycle Schizogony Sporogony Sporozoites Mosquito Salivary Gland Gametocytes Oocyst Erythrocytic Cycle Zygote Hypnozoites (for P. vivax and P. ovale )
    30. 32. Exo-erythrocytic (tissue) phase <ul><li>P. malariae or P. falciparum sporozoites do not form hypnotizes , develop directly into pre-erythrocytic schizonts in the liver </li></ul><ul><li>Pre-erythrocytic schizogeny takes 6-16 days post infection </li></ul><ul><li>Schizonts rupture, releasing merozoites which invade red blood cells (RBC) in liver </li></ul>
    31. 33. Affinity of Parasite to Erythrocytes <ul><li>P.vivax </li></ul><ul><li>P.malariae Infectes only young or </li></ul><ul><li>P.ovale Old Erythocytes </li></ul><ul><li>P.falciparum Infects all ages of RBC </li></ul><ul><li>Also adhere to the endothelial lining of Blood vessesl </li></ul><ul><li>Causes the obstruction, Thrombosis and Local Ischemias </li></ul>
    32. 35. Erythrocyte cycle <ul><li>Merozoites released invade red cells </li></ul><ul><li>P.vivax infects young erythrocytes </li></ul><ul><li>P.malariae Infects old erythrocytes </li></ul><ul><li>P.falciparum infects RBC of all ages </li></ul><ul><li>The Merozoites are pear shaped 1-5 microns in length </li></ul><ul><li>The receptors for Merozoites are on red cells in the glycoprotein </li></ul><ul><li>Doctortvrao’s ‘e’ learning series </li></ul>
    33. 36. Erythrocytic Schizogony <ul><li>Liberated Merozoites penetrate RBC </li></ul><ul><li>Three stages occur </li></ul><ul><li>1 Trophozoites </li></ul><ul><li>2 Schizont </li></ul><ul><li>3 Merozoite </li></ul>
    34. 37. Erythrocytic cycle <ul><li>Ruptured red cells release Merozoites which attack new red cells </li></ul><ul><li>Continue with Schizogony </li></ul><ul><li>Repeated cycles will continue </li></ul><ul><li>In P.falciparum - infected erythrocytes with Schizonts aggregate in the capillaries of brain and other internal organs </li></ul><ul><li>Only ring forms are seen in the blood smears </li></ul>
    35. 38. Trophozoites <ul><li>After invasion grow and feed on hemoglobin </li></ul><ul><li>Blue cytoplasm and red nucleus, Called as Signet ring appearance </li></ul><ul><li>Hence called ring form </li></ul>
    36. 39. Schizont <ul><li>When the Trophozoite is fully developed becomes compact. </li></ul><ul><li>Malarial pigments are scattered through the cytoplasm </li></ul><ul><li>The Nucleus is large and lies at the periphery starts dividing. </li></ul><ul><li>Becomes Schizont </li></ul><ul><li>Doctortvrao’s ‘e’ learning series </li></ul>
    37. 40. Plasmodium vivax <ul><li>Number of merozoites 12 to 24 arranged in grape like clusters </li></ul><ul><li>RBC enlarged </li></ul><ul><li>Schuffner’s dots present </li></ul><ul><li>Yellowish brown fine granules </li></ul><ul><li>Schizont 9-10 microns fills and enlarged Red cell </li></ul><ul><li>Gametocytes – spherical or globular </li></ul><ul><li>Size much larger than red cell </li></ul><ul><li>Male 9 microns </li></ul><ul><li>Female 10 – 11 microns </li></ul><ul><li>Doctortvrao’s ‘e’ learning series </li></ul>
    38. 41. Plasmodium falciparum <ul><li>RBC is normal size </li></ul><ul><li>Maurer’s dots 9 large red spots sometimes basophilic stippling </li></ul><ul><li>Dark brown or blackish one or two solid blocks </li></ul><ul><li>Gametocytes Crescentric, larger than a red cell 9 -10 microns, male and female 12- 14 microns </li></ul>
    39. 42. Plasmodium malaria <ul><li>RBC Normal size </li></ul><ul><li>Contain Ziemann’s stippling </li></ul><ul><li>Contain dark brown coarse granules </li></ul><ul><li>Schizont – 6 – 7 microns almost fills a normal sized red cell. </li></ul><ul><li>Gametocytes Spherical or globular </li></ul><ul><li>Size much larger than a red cell </li></ul>
    40. 43. Plasmodium ovale <ul><li>Infected RBC slightly larger </li></ul><ul><li>Contain Schuffner’s dots coarse granules </li></ul><ul><li>Schizont 6.2 microns fills three quarters </li></ul><ul><li>Merozoites 6 -12 fills three quarters </li></ul><ul><li>Gametocytes Spherical or globular, much larger than a red cell </li></ul><ul><li>Doctortvrao’s ‘e’ learning series </li></ul>
    41. 54. Exo-erythrocytic (tissue) phase <ul><li>P. malariae or P. falciparum sporozoites do not form hypnozites, develop directly into pre-erythrocytic schizonts in the liver </li></ul><ul><li>Pre-erythrocytic schizogeny takes 6-16 days post infection </li></ul><ul><li>Schizonts rupture, releasing merozoites which invade red blood cells (RBC) in liver </li></ul>
    42. 55. Exo Erythrocytic Schizogony <ul><li>Some Sprozoites do not undergo sporogony in the first instance </li></ul><ul><li>But go into resting stage called as Hypnozoites,( hibernation ) </li></ul><ul><li>Within 2 years reactivate to form Schizonts release Merozoites and attack red cell and produce relapses </li></ul><ul><li>Absent in P falciparum </li></ul><ul><li>Doctortvrao’s ‘e’ learning series </li></ul>
    43. 56. Gametogony <ul><li>Merozoites differentiate into Male and female gametocytes </li></ul><ul><li>Macrogametocytes also called female gametocytes </li></ul><ul><li>Microgametocyte also called as male gametocytes </li></ul><ul><li>They develop in the red cells </li></ul><ul><li>Found in the peripheral blood smears </li></ul><ul><li>Microgametocyte of all species are similar in size </li></ul><ul><li>Macro gametocytes are larger in size. </li></ul>
    44. 58. Mosquito cycle A definitive Host – Mosquito
    45. 59. Mosquito cycle Sexual cycle <ul><li>Sexual cycle will be initiated in the Humans by the formation of Gametocytes </li></ul><ul><li>Develop further in the female Anopheles Mosquito </li></ul><ul><li>Only mature sexual forms are capable of further development in Mosquito </li></ul><ul><li>In midgut one Microgametocyte develops into 4-8 thread like filamentous structures named Micro gametes </li></ul><ul><li>From one macrogametocyte only one macrogamete is formed </li></ul>
    46. 60. Events in Mosquitos <ul><li>Fertilization occurs when a Microgametocyte penetrate into Macrogametocyte </li></ul><ul><li>Fertilized macrogametocyte is known as ZYGOTE </li></ul><ul><li>ZYGOTE matures into OOKINETE </li></ul><ul><li>OOKINETE to OOCYST </li></ul>
    47. 61. Formation of Sporozoites in Mosquitos. <ul><li>OOCYST matures with large number of Sporozoites ( A few hundred to thousands.) </li></ul><ul><li>OOCYST ruptures and release SPOROZOITES in the body cavity of Mosquito </li></ul><ul><li>There is a specific predilection for salivary glands </li></ul><ul><li>Now capable to transmit the infection to new Host </li></ul><ul><li>Doctortvrao’s ‘e’ learning series </li></ul>
    48. 62. Pathology and Pathogenesis <ul><li>Sporozoites result from sexaul and sporogenic cycle of development in mosquitoes and injected into human blood serum. </li></ul><ul><li>Events start with bite of Infected Anopheles Mosquitoes </li></ul><ul><li>Sporoozoites enter liver, in 1 hour infect the parenchymal cell. </li></ul>
    49. 63. Pathology and Pathogenesis <ul><li>Sporozoites result from sexaul and sporogenic cycle of development in mosquitoes and injected into human blood serum. </li></ul><ul><li>Events start with bite of Infected Anopheles Mosquitoes </li></ul><ul><li>Sporoozoites enter liver, in 1 hour infect the parenchymal cell. </li></ul>
    50. 64. Pathogenesis in Pre Erythrocyte cycle <ul><li>Numerous asexual progeny – Merozoites ruputure and leave from liver cells </li></ul><ul><li>Enter the Blood and invade Erythrocytes </li></ul><ul><li>Erythrocytic cycle starts – Multiply in species specific fashion </li></ul><ul><li>Broods of Merozoites appearing at 48 hour interval in P.ovale, P.vivax , P.falciparum </li></ul><ul><li>P.malariae appear in 72 hour cycles , </li></ul>
    51. 65. Chooses to enter the RBC <ul><li>Specific for each species </li></ul><ul><li>They pit on red cells </li></ul><ul><li>By endocytosis enters the RBC </li></ul><ul><li>Becomes a Trophozoites </li></ul>
    52. 66. Schizont <ul><li>When the T rophozoite is fully developed becomes compact. </li></ul><ul><li>Malarial pigments are scattered through the cytoplasm </li></ul><ul><li>The Nucleus is large and lies at the periphery starts dividing. </li></ul><ul><li>Becomes Schizont </li></ul><ul><li>Doctortvrao’s ‘e’ learning series </li></ul>
    53. 67. Cycles differs in Different species <ul><li>Cycle repeats every 48 hours in </li></ul><ul><li>1 P.falciparum </li></ul><ul><li>2 P.ovale </li></ul><ul><li>3 P.vivax </li></ul><ul><li>Repeats every 72 hours In </li></ul><ul><li>P.malariae </li></ul><ul><li>Doctortvrao’s ‘e’ learning series </li></ul>
    54. 68. Incubation period varies according to species <ul><li>Which includes Exo eythrocytic cycle time and one or two erythocytic cycles, </li></ul><ul><li>P.vivax and P.falciparum 10 – 15 days (can vary from weeks to months) </li></ul><ul><li>P.malariae infection can start after 28 days. </li></ul><ul><li>Doctortvrao’s ‘e’ learning series </li></ul>
    55. 69. Clinical Features of Malaria
    56. 70. Clinical Manifestations are related to cycle of events in relation to RBC
    57. 71. How Malaria present Clinically <ul><li>Stage 1 </li></ul><ul><li>Chills for 15 mt to 1 hour </li></ul><ul><li>Caused due to rupture from the host red cells escape into Blood </li></ul><ul><li>Preset with nausea, vomitting,headache </li></ul><ul><ul><li>Stage 2 </li></ul></ul><ul><li>Fever may reach upto 40 0 c may last for several hours starts invading newer red cells. </li></ul>
    58. 72. Clinical Malaria <ul><li>Stage 3 </li></ul><ul><li>Patent starts sweating, concludes the episode </li></ul><ul><li>Cycles are frequently Asynchronous </li></ul><ul><li>Paroxysms occur every 48 – 72 hours </li></ul><ul><li>In P.malariae pyrexia may lost for 8 hours or more and temperature my exceed 41 0 c </li></ul><ul><li>Doctortvrao’s ‘e’ learning series </li></ul>
    59. 73. More commonly, the patient presents with a combination of the following symptoms <ul><li>Fever </li></ul><ul><li>Chills </li></ul><ul><li>Sweats </li></ul><ul><li>Headaches </li></ul><ul><li>Nausea and vomiting </li></ul><ul><li>Body aches </li></ul><ul><li>General malaise. </li></ul><ul><li>Doctortvrao’s e learning </li></ul>
    60. 74. Early symptoms <ul><li>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. </li></ul>
    61. 75. What are the characteristics of a malaria attack <ul><li>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. </li></ul><ul><li>A poor general condition, feeling unwell and having headaches like influenza. </li></ul><ul><li>Diarrhea, nausea and vomiting often occur as well. </li></ul><ul><li>Doctortvrao’s ‘e’ learning series </li></ul>
    62. 76. Malaria the disease <ul><li>9-14 day incubation period </li></ul><ul><li>Fever, chills, headache, back and joint pain </li></ul><ul><li>Gastrointestinal symptoms (nausea, vomiting, etc.) </li></ul>
    63. 77. Clinical events <ul><li>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 </li></ul><ul><li>Doctortvrao’s ‘e’ learning series </li></ul>
    64. 78. Malaria stages of the disease
    65. 79. Malaria intensifies <ul><li>Symptoms intensify </li></ul><ul><li>Irregular high fever </li></ul><ul><li>Anxiety, delirium and other mental problems </li></ul><ul><li>Sweating, increased pulse rate, severe exhaustion </li></ul><ul><li>Worsening GI symptoms </li></ul><ul><li>Enlarged spleen and liver </li></ul>
    66. 80. Broad clinical manifestations of Malaria <ul><li>Fever </li></ul><ul><li>Sweating </li></ul><ul><li>Anemia </li></ul><ul><li>Splenomagaly (enlarged spleen) </li></ul><ul><li>Irratability </li></ul><ul><li>Coma, Retinal Hemorrages  </li></ul><ul><li>Algid Malaria ( a shocklike syndrome) </li></ul><ul><li>Respiratory distress syndrome </li></ul>
    67. 81. Periodicity can be clue in Diagnosis and species relation <ul><li>Malaria tertiana: 48h between fevers (P. vivax and ovale) </li></ul><ul><li>Malaria quartana: 72h between fevers (P. malariae) </li></ul><ul><li>Malaria tropica: irregular high fever (P. falciparum) </li></ul>
    68. 82. Malaria the disease
    69. 83. Pathogenesis of Malaria <ul><li>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) </li></ul><ul><li>Doctortvrao’s ‘e’ learning series </li></ul>
    70. 84. Cytokines & toxins <ul><li>Hatched=chill </li></ul><ul><li>Black=rigor </li></ul><ul><li>Clear=sweating </li></ul><ul><li>Malaria produces a strong Th-1 type response </li></ul><ul><li>Elevated serum levels of IFN  and TNF  </li></ul><ul><li>Cytokines can induce (mimic) many of the symptoms and signs of malaria (shivering, headache, chills, spiking fever, sweating, vasodilation, hypoglycemia) </li></ul>
    71. 85. Cerebral Malaria <ul><li>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. </li></ul>
    72. 86. Cerebral Malaria <ul><li>Present with Hyperpyrexia </li></ul><ul><li>Can lead to Coma </li></ul><ul><li>Paralysis and other complications. </li></ul><ul><li>Brain appears congested </li></ul>
    73. 87. Pathogenesis of Cerebral malaria <ul><li>High cytokine levels could be toxic on their own </li></ul><ul><li>High levels of cytokine also enhance the second process thought to be responsible for cerebral malaria: sequestration of infected RBCs </li></ul>
    74. 88. Sequestration & cytoadherence <ul><li>Rosetting (adhesion of infected RBCs to other RBCs) and clumping (adhesion between infected cells) was first observed in in vitro culture </li></ul><ul><li>Rosetting was also found in 50% of field isolates and correlated strongly with the severity of the observed disease </li></ul>
    75. 89. Sequestration & cytoadherence <ul><li>How do parasite proteins travel to the surface of the RBC? </li></ul><ul><li>This is a considerable challenge as RBC lack functional secretory apparatus </li></ul><ul><li>Why do patients fail to mount an effective immune response against antigens that are presented this prominently? </li></ul>
    76. 90. Black Water Fever <ul><li>In malignant malaria a large number of the red blood corpuscles are destroyed. Haemoglobin from the blood corpuscles is excreted in the urine, which therefore is dark and almost the colour of cola </li></ul>
    77. 91. How long Malaria infection can lost in Man <ul><li>Without treatment P.falciparum will terminate in less than 1 year. </li></ul><ul><li>But in P.vivax and P.ovale persist as hypnozoites after the parasites have disppeared from blood. </li></ul><ul><li>Can prodce periodic relapses upto 5 years </li></ul><ul><li>In P.malariae may last for 40 years </li></ul><ul><li>( Called as recrudescence X relapse ) </li></ul><ul><li>Parasites survive in erythrocytes Liver ? </li></ul><ul><li>Doctortvrao’s ‘e’ learning series </li></ul>
    78. 92. Why Falciparum Infections are Dangerous <ul><li>Can produce fatal complications, </li></ul><ul><li>1.Cerebral malaria </li></ul><ul><li>2.Malarial hyperpyrexia </li></ul><ul><li>3.Gastrointestinal disorders. </li></ul><ul><li>4.Algid malaria </li></ul><ul><li>5 Black water fever can lead to death </li></ul><ul><li>Doctortvrao’s ‘e’ learning series </li></ul>
    79. 93. Complication of P.malariae <ul><li>Can produce Nephrotic syndrome </li></ul><ul><li>Affects mainly children of years age </li></ul>
    80. 94. Pernicious Malaria Carries a High Mortality <ul><li>On few occasions life threading complications can occur. </li></ul><ul><li>Occurs in infections with P.falciparum </li></ul><ul><li>Associated with Heavy parasitaztion </li></ul><ul><li>Grouped into three types </li></ul><ul><li>1. Cerebral Malaria </li></ul><ul><li>2 Algid malaria </li></ul><ul><li>3 Black water fever </li></ul>
    81. 95. Uncomplicated Malaria <ul><li>The classical (but rarely observed) malaria attack lasts 6-10 hours. It consists of: </li></ul><ul><li>a cold stage (sensation of cold, shivering) </li></ul><ul><li>a hot stage (fever, headaches, vomiting; seizures in young children) </li></ul><ul><li>and finally a sweating stage (sweats, return to normal temperature, tiredness) </li></ul><ul><li>Doctortvrao’s ‘e’ learning series </li></ul>
    82. 96. Malaria A Major Health problem of Tropical countreis
    83. 97. Pernicious Malaria <ul><li>Is a life threatening complication in acute falciparum malaria </li></ul><ul><li>It is due to heavy parasitization </li></ul><ul><li>Manifest with </li></ul><ul><li>1 Cerebral malaria – it presents with hyperpyrexia, coma and paralysis. Brain is congested </li></ul><ul><li>2 Algid malaria – presents with clammy skin leading to peripheral circulatory failure. </li></ul>
    84. 98. Complication in Malaria <ul><li>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 </li></ul><ul><li>Abnormalities in blood coagulation and thrombocytopenia (decrease in blood platelets) </li></ul><ul><li>Cardiovascular collapse and shock </li></ul>
    85. 99. Black water Fever <ul><li>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 </li></ul><ul><li>It is characterized by intravascular hemolysis fever, and Haemoglobunuria </li></ul><ul><li>Cardiovascular collapse and shock </li></ul><ul><li>Abnormalities in blood coagulation and thrombocytopenia (decrease in blood platelets) </li></ul>
    86. 100. Other Complications In Malaria <ul><li>Acute kidney failure </li></ul><ul><li>Hyperparasitemia, where more than 5% of the red blood cells are infected by malaria parasites </li></ul><ul><li>Metabolic acidosis (excessive acidity in the blood and tissue fluids), often in association with hypoglycemia </li></ul>
    87. 101. Immunity <ul><li>Influenced by </li></ul><ul><ul><li>Genetics </li></ul></ul><ul><ul><li>Age </li></ul></ul><ul><ul><li>Health condition </li></ul></ul><ul><ul><li>Pregnancy status </li></ul></ul><ul><ul><li>Intensity of transmission in region </li></ul></ul><ul><ul><li>Length of exposure </li></ul></ul><ul><ul><li>Maintenance of exposure </li></ul></ul>
    88. 102. Immunity <ul><li>Innate </li></ul><ul><ul><li>Red cell polymorphisms associated with some protection </li></ul></ul><ul><ul><ul><li>Hemoglobin S sickle cell trait or disease </li></ul></ul></ul><ul><ul><ul><li>Hemoglobin C and hemoglobin E </li></ul></ul></ul><ul><ul><ul><li>Thalessemia – α and β </li></ul></ul></ul><ul><ul><ul><li>Glucose – 6 – phosphate dehydrogenase deficiency (G6PD) </li></ul></ul></ul><ul><ul><li>Red cell membrane changes </li></ul></ul><ul><ul><ul><li>Absence of certain Duffy coat antigens improves resistance to P.v. </li></ul></ul></ul>
    89. 103. Immunity <ul><li>Acquired </li></ul><ul><ul><li>Transferred from mother to child </li></ul></ul><ul><ul><ul><li>3-6 months protection </li></ul></ul></ul><ul><ul><ul><li>Then children have increased susceptibility </li></ul></ul></ul><ul><ul><li>Increased susceptibility during early childhood </li></ul></ul><ul><ul><ul><li>Hyper- and holoendemic areas </li></ul></ul></ul><ul><ul><ul><ul><li>By age 5 attacks usually < frequent and severe </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Can have > parasite densities with fewer symptoms </li></ul></ul></ul></ul><ul><ul><ul><li>Meso- or hypoendemic areas </li></ul></ul></ul><ul><ul><ul><ul><li>Less transmission and repeated attacks </li></ul></ul></ul></ul><ul><ul><ul><ul><li>May acquire partial immunity and be at higher risk for symptomatic disease as adults </li></ul></ul></ul></ul>
    90. 104. Immunity <ul><li>Acquired </li></ul><ul><ul><li>No complete immunity </li></ul></ul><ul><ul><ul><li>Can be parasitemic without clinical disease </li></ul></ul></ul><ul><ul><li>Need long period of exposure for induction </li></ul></ul><ul><ul><li>May need continued exposure for maintenance </li></ul></ul><ul><ul><li>Immunity can be unstable </li></ul></ul><ul><ul><ul><li>Can wane as one spends time outside endemic area </li></ul></ul></ul><ul><ul><ul><li>Can change with movement to area with different endemicity </li></ul></ul></ul><ul><ul><ul><li>Decreases during pregnancy, risk improves with increasing gravidity </li></ul></ul></ul>
    91. 105. Laboratory Diagnosis of Malaria
    92. 106. Diagnostic Tools for Human Infections with Malaria <ul><li>Blood film examination </li></ul><ul><li>Serology - IFA </li></ul><ul><li>PCR </li></ul>
    93. 107. Blood collected with sterile technique
    94. 108. Making the smears
    95. 109. Making of Thick smear
    96. 110. Thin and Thick smear
    97. 111. Appearance of Thick and Thin Smears
    98. 112. Microscopy <ul><li>Malaria parasites can be identified by examining under the microscope a drop of the patient's blood, spread out as a &quot;blood smear&quot; 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 </li></ul><ul><li>Doctortvrao’s ‘e’ learning series </li></ul>
    99. 113. How parasites appear
    100. 116. QBC system has evolved as rapid and precise method in Diagnosis <ul><li>The QBC Malaria method is the simplest and most sensitive method for diagnosing the following diseases. </li></ul><ul><ul><li>Malaria </li></ul></ul><ul><ul><li>Babesiosis </li></ul></ul><ul><ul><li>Trypanosomiasis (Chagas disease, Sleeping Sickness) </li></ul></ul><ul><ul><li>Filariasis (Elephantiasis, Loa-Loa) </li></ul></ul><ul><ul><li>Relapsing Fever (Borreliosis) </li></ul></ul><ul><ul><li>Doctortvrao’s ‘e’ learning series </li></ul></ul>
    101. 117. QBC system
    102. 118. Appearance of Malarial parasite in QBC system
    103. 119. Antigen Detection Methods are Rapid and Precise <ul><li>Antigen Detection </li></ul><ul><li>Various test kits are available to detect antigens derived from malaria parasites. Such immunologic (&quot;immunochromatographic&quot;) tests most often use a dipstick or cassette format, and provide results in 2-15 minutes. These &quot;Rapid Diagnostic Tests&quot; (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 </li></ul>
    104. 120. Serology <ul><li>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. </li></ul><ul><li>Doctortvrao’s ‘e’ learning series </li></ul>
    105. 121. Newer Diagnostic methods <ul><li>Molecular Diagnosis </li></ul><ul><li>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). </li></ul>
    106. 122. Types of Serological Assays Malaria Antibody Detection Indirect Fluorescent Antibody Enzyme immunoassays Antigen Detection Immunochromatographic
    107. 123. Antibody Detection = Antigen-antibody complex Patient’s serum contains specific and non-specific antibodies + Antigen
    108. 124. Antibody Detection * -labeled antibody to human antibody + Antigen-antibody- * antibody complex = Antigen-antibody complex
    109. 125. Indirect Fluorescent Antibody (IFA) Microscope slide
    110. 126. Enzyme Immunoassay (EIA/ELISA ) _ + enzyme substrate
    111. 127. ELISA
    112. 128. Antigen Detection Monoclonal antibody = Antigen-antibody complex + Antigen in patient’s serum
    113. 129. Antigen Detection = Antibody-antigen-antibody complex + Immobilized monoclonal antibody Antigen-antibody complex
    114. 130. Antigen Detection Malaria Immunochromatographic Dipstick Optimal Assay Control Plasmodium pan specific monoclonal antibody P. falciparum specific monoclonal antibody
    115. 131. Malaria IFA Test <ul><li>Sensitivity = 98% </li></ul><ul><li>Specificity = 99.5% </li></ul><ul><li>Sulzer et al, Am J Trop Med Hyg 1969;18:199-205 </li></ul><ul><li>Sulzer et al, Bull Wld Hlth Org 1971;45:375-379 </li></ul>
    116. 132. P. malaria
    117. 133. Malaria IFA Test Initial detection of antibodies <ul><li>Parasitemia precedes antibody </li></ul><ul><li>P. vivax 2-6 days </li></ul><ul><ul><li>P. falciparum and P. malariae 4-6 days </li></ul></ul><ul><li>If parasitemia is suppressed by treatment, may develop detectable antibody </li></ul>
    118. 134. Malaria IFA Test Determination of Infecting Species <ul><li>Non-Immune </li></ul><ul><li>Samples drawn 0-14 days post onset: Highest titer was to the infecting species in 81% </li></ul><ul><li>Samples drawn 15-60 days post onset: Highest titer was to the infecting species in 96% </li></ul>
    119. 135. Malaria IFA Test Determination of Infecting Species <ul><li>Is possible in non-immune individuals with primary infection. </li></ul><ul><li>Is NOT possible in immune individuals because their antibody response reflects multiple infections with multiple species. </li></ul>
    120. 136. Malaria IFA Test Antibody Persistence after Treatment <ul><li>Non-Immunes (Vietnam Vets with Pv) </li></ul><ul><li>53% IFA negative at 6 mo. post-Rx </li></ul><ul><li>59% IFA negative at 12 mo. post-Rx </li></ul><ul><li>Wilson et al, Am J Trop Med Hyg 1970;19:401-404 </li></ul>
    121. 137. Malaria IFA Test Antibody Persistence after Treatment <ul><li>Non-Immunes (Vietnam Vets with Pv) </li></ul><ul><li>53% IFA negative at 6 mo. post-Rx </li></ul><ul><li>59% IFA negative at 12 mo. post-Rx </li></ul><ul><li>Wilson et al, Am J Trop Med Hyg 1970;19:401-404 </li></ul>
    122. 138. Sensitivity of Tools for Diagnosis of Malarial Infection <ul><li>Most sensitive: </li></ul><ul><li> Antibody detection </li></ul><ul><li>2. PCR </li></ul><ul><li>3. Blood film examination </li></ul>
    123. 139. Diagnosis of Untreated Acute Malaria <ul><li>Blood film examination </li></ul><ul><li>PCR </li></ul>
    124. 140. Diagnosis of Chronic Malaria <ul><li>Screen with serology </li></ul><ul><li>If IFA positive: </li></ul><ul><li>May do blood film examination </li></ul><ul><li>May do PCR </li></ul><ul><li>Doctortvrao’s ‘e’ learning series </li></ul>
    125. 141. Diagnosis of Treated Recent Malaria <ul><li>Serology </li></ul><ul><li>Blood film examination </li></ul><ul><li>PCR </li></ul>
    126. 142. Malaria Relapses <ul><li>In P. vivax and P. ovale infections, patients having recovered from the first episode of illness may suffer several additional attacks (&quot;relapses&quot;) after months or even years without symptoms. Relapses occur because P. vivax and P. ovale have dormant liver stage parasites (&quot;hypnozoites&quot;) that may reactivate. Treatment to reduce the chance of such relapses is available and should follow treatment of the first attack. </li></ul>
    127. 143. Treatment
    128. 144. Over view of Treatment options in Malaria <ul><li>Most drugs used in treatment are active against the parasite forms in the blood (the form that causes disease) and include: </li></ul><ul><li>Chloroquine </li></ul><ul><li>Sulfadoxine-pyrimethamine (Fansidar®) </li></ul><ul><li>Mefloquine (Lariam®) </li></ul><ul><li>Atovaquone-proguanil (Malarone®) </li></ul><ul><li>Quinine </li></ul><ul><li>Doxycycline </li></ul><ul><li>Artemisin derivatives (not licensed for use in the United States, but often found overseas) </li></ul>
    129. 145. World Health Organization Recommends <ul><li>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. </li></ul><ul><li>Doctortvrao’s ‘e’ learning series </li></ul>
    130. 146. What is Presumptive Treatment? <ul><li>Presumption - In an area with high transmission of malaria, it should be presumed that ALL cases of fever are due to malaria. </li></ul><ul><li>Treatment - First loading dose of Chloroquine should be administered immediately after collecting the blood specimen, even without waiting for its report. </li></ul><ul><li>If the fever is indeed malaria, this treatment alleviates symptoms early, may be well before the test result is available. </li></ul><ul><li>If it is malaria, Chloroquine also prevents the spread of malaria by destroying the gametocytes of P. vivax (the more common malaria). </li></ul><ul><li>If it is not malaria, nothing is lost, for Chloroquine at this dose is safe and has no adverse effects! </li></ul>
    131. 147. Radical treatment <ul><li>Radical treatment is administration of Primaquin to all confirmed cases of malaria. </li></ul><ul><li>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. </li></ul><ul><li>In P. falciparum malaria, a single dose of primaquine destroys the gametocytes, thereby prevents the spread of the infection into the mosquito. </li></ul>
    132. 148. Use of Primaquin <ul><li>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. </li></ul><ul><li>Doctortvrao’s ‘e’ learning series </li></ul>
    133. 149. Drug Resistance
    134. 150. Choroquine Resistance <ul><li>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 </li></ul>
    135. 151. Chloroquine Resistance <ul><li>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. </li></ul>
    136. 152. Testing Drug Resistance <ul><li>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 </li></ul><ul><li>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. </li></ul><ul><li>Doctortvrao’s ‘e’ learning series </li></ul>
    137. 153. In vitro Testing <ul><li>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. </li></ul>
    138. 154. Molecular Methods <ul><li>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 </li></ul>
    139. 155. <ul><li>Resistance to Chloroquine - 1960 </li></ul>
    140. 156. <ul><li>Resistance to Chloroquine - 1970 </li></ul>
    141. 157. <ul><li>Resistance to Chloroquine - 1980 </li></ul>
    142. 158. <ul><li>Resistance to Chloroquine - 2000 </li></ul>
    143. 159. <ul><li>Intensification of Chloroquine </li></ul><ul><li>Resistance in Africa </li></ul>
    144. 160. <ul><li>Antimalarials Resistance - 1998 </li></ul><ul><li>(excluding CQ) </li></ul>SP, Mefloquine, Halofantrine, Quinine SP Mefloquine SP, Mefloquine
    145. 161. <ul><li>Reports of Chloroquine Resistance </li></ul><ul><li>in P.vivax </li></ul>1989 1990 1995 1995 1991 1995
    146. 162. World Malaria Day, April 25 <ul><li>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 &quot;Counting Malaria Out.&quot; How does CDC contribute? </li></ul>
    147. 163. CDC's malaria Web site offers telediagnosis and treatment strategies <ul><li>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, </li></ul>
    148. 164. Tele Net Working <ul><li>Images of other suspected parasitic infections can be e-mailed to the CDC's Laboratory Identification of Parasites of Public Health Concern program ( ). </li></ul><ul><li>Doctortvrao’s ‘e’ learning series </li></ul>
    149. 165. Development of Vaccines <ul><li>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. </li></ul>
    150. 166. Future Ambitions <ul><li>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. </li></ul>
    151. 168. Why vaccines are Difficult <ul><li>No licensed vaccine against malaria currently exists </li></ul><ul><li>The parasite has evolved a series of strategies that allow it to confuse, hide, and misdirect the human immune system. </li></ul><ul><li>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. </li></ul>
    152. 169. Simple protective Measures
    153. 170. Bill and Melinda Gates Foundation that announced last year it was donating £115 million to help develop a vaccine for the deadly disease.
    154. 171. Goal of Humanity
    155. 172. Goals to achieve Control Malaria <ul><li>World Malaria Day is 25th April. On this day two years ago, UN Secretary-General Ban Ki-moon put forward what he described as a bold but achievable vision – “to put a stop to malaria deaths by ensuring universal coverage [of malaria control measures] by the end of 2010”. But there is still a long way to go before all those who live in malaria-endemic regions are reached by the initiatives referred to by the Secretary-General: indoor residual spraying, bed nets treated with long-lasting insecticide, access at all public health facilities to effective malaria treatment and diagnosis, and community health workers trained in dealing with malaria. </li></ul>
    156. 173. Malaria on Twitter and Facebook <ul><li>The U.S. Fund for UNICEF today announced that in commemoration of World Malaria Day 2010 (April 25th), it will be partnering with a unique social media initiative anchored on Twitter and Facebook and meant to mobilize action toward achieving the United Nations' (UN) goal of providing all endemic African countries with malaria control interventions by the end of 2010. </li></ul>
    157. 174. Created by Dr.T.V.Rao MD for ‘e’ Learning. Email [email_address]