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  • What is the malaria vector? Malaria is spread by the bite of an infected female anopheline mosquito. In Africa, most malaria is spread by the A. gambiae. These mosquitoes bite at night, with a primary feeding time between 10:00 pm and 2:00 am. They are primarily an indoor biting mosquito. The picture on the left shows a number of Anopheles mosquitoes that were collected from a house in Kinshasa. If you look closely, you will notice some nice, fat mosquitoes that are quite well fed, presumably on the inhabitants of that house. The fat mosquitoes are the females. Female Anopheles mosquitoes require a blood meal to produce their eggs. You will also notice some very skinny mosquitoes. Those are the males. As a bloodmeal is needed for the female to produce her eggs, it is only the female that feeds on people. In the picture on the right, you can see several skinny larvae in their natural habitat. It takes about a week for larvae to develop and emerge as adult mosquitoes.
  • There are four species of malaria that infect humans. All of them are transmitted in the same way, so I will explain the malaria lifecycle. Mosquito bites human Sporozoites injected into human host during blood meal Sporozoites infect liver cells, develop into schizonts, which release merozoites into the blood stream by rupturing the liver cells. Merozoites penetrate red blood cells and form schizonts; red blood cells release merozoites Some merozoites differentiate into male gametocytes or female gametocytes. Gametocytes are taken in by mosquito from a blood meal. Parasites undergo sexual reproduction, develop into oocysts which release sporozoites that invade the mosquito's salivary glands. And the cycle continues on……
  • Once the parasite has entered the body, there are 2 main ways that malaria kills. Anemia. Malaria parasites destroy red blood cells, increasing anemia in populations that are already malnourished and anemic. Sustained moderate to severe anemia is associated with increased mortality. Cerebral malaria is the other major killer. It can kill very quickly. It is a type of complication of malaria in which the red blood cells obstruct the blood vessels in the brain. Other vital organs can also be damaged. has a fatality rate of 15% or more, even when treated and is extremely serious.
  • Combining two or more antimalarial drugs with different modes of action (and thus drug targets) provides two main advantages. First cure rates are usually increased. Second, in the rare event that a mutant parasite which is resistant to one of the drugs arises de-novo during the course of the infection, it will be killed by the other drug. This mutual protection prevents the emergence of resistance. For both these advantages it is necessary that both partner drugs in a combination are independently effective. Balanced against these two advantages are the increased costs and the increased risks of adverse effects (although in some cases such as the combination of artesunate + mefloquine adverse effects such as vomiting are reduced).
  • Malaria

    1. 1. Pugud Samodro Bag/SMF Ilmu Penyakit Dalam FKIK Unsoed/ RSUD Prof Margono Soekarjo Purwokerto
    2. 2. What is Malaria? <ul><li>Parasitic infection of human red blood cells </li></ul><ul><li>4 species can infect humans </li></ul><ul><ul><li>Plasmodium falciparum </li></ul></ul><ul><ul><li>Plasmodium vivax </li></ul></ul><ul><ul><li>Plasmodium malariae </li></ul></ul><ul><ul><li>Plasmodium ovale </li></ul></ul>Pictures of P. falciparum
    3. 3. Etiology <ul><li>Causative organism: Plasmodia </li></ul><ul><ul><li>P. Vivax: tertian malaria </li></ul></ul><ul><ul><li>P. Malariae: quartan malaria </li></ul></ul><ul><ul><li>P. Falciparum: malignant malaria </li></ul></ul><ul><ul><li>P. Ovale: tertian malaria </li></ul></ul><ul><li>Pathogenicity: merozoite, malarial pigment & </li></ul><ul><li>products of metabolism </li></ul>
    4. 4. Plasmodium falciparum <ul><li>Most dangerous form of malaria </li></ul><ul><ul><li>Risk of cerebral malaria, renal failure, acute respiratory distress syndrome, severe anemia </li></ul></ul><ul><li>Prompt treatment is essential </li></ul><ul><li>Untreated infection in a non-immune person would likely be fatal </li></ul><ul><li>Once person is treated and cured, there is no risk of relapse (but you can get infected again…) </li></ul><ul><ul><li>P. falciparum has no dormant liver stage (hypnozoite) </li></ul></ul>
    5. 5. P. vivax and P. ovale <ul><li>Less likely to be life threatening than P. falciparum </li></ul><ul><li>Symptoms (especially fever) can still be dramatic </li></ul><ul><li>Different drugs are used to treat blood and liver stage parasites </li></ul>
    6. 6. Etiology <ul><li>Two period: </li></ul><ul><ul><li>human - whole asexual reproduction </li></ul></ul><ul><ul><li>mosquito - sexual parasitic stage </li></ul></ul><ul><li>Two host: </li></ul><ul><ul><li>human - intermediate host </li></ul></ul><ul><ul><li>mosquito - final host </li></ul></ul><ul><li>notes: </li></ul><ul><ul><li>clinical symptoms: erythrocytic stage </li></ul></ul><ul><ul><li>relapse: exerythrocytic stage </li></ul></ul><ul><ul><li>infectivity: sporozoite </li></ul></ul>
    7. 7. Epidemiology <ul><li>Source of infection </li></ul><ul><ul><li>Patient, parasite carrier </li></ul></ul><ul><li>Route of transmission </li></ul><ul><ul><li>female mosquito biting person </li></ul></ul><ul><ul><li>blood transfusion </li></ul></ul><ul><li>Susceptibility: </li></ul><ul><ul><li>universal susceptibility </li></ul></ul><ul><ul><li>no-cross-immunity </li></ul></ul><ul><ul><li>re-infection </li></ul></ul><ul><li>Epidemic features: </li></ul><ul><ul><li>sporadic or endemic, tropic or subtropic </li></ul></ul>
    8. 8. What is the Malaria Vector? <ul><li>Spread by bite of infected female Anopheles mosquitoes </li></ul><ul><li>Night-biting mosquitoes </li></ul><ul><li>Indoor-biting mosquitoes </li></ul>
    9. 9. Pathogenesis <ul><li>Mechanism of attack </li></ul><ul><li>merozoite </li></ul><ul><li>RBC rupture malaria pigment </li></ul><ul><li>products of metabolism </li></ul><ul><li>blood stream allergy </li></ul><ul><li>P. Falciparum: produce microvascular disease </li></ul><ul><li>magnitude of the parasitemia & age of patient </li></ul><ul><li>no specific Ab or cell -mediated response </li></ul>
    10. 10. Malaria Lifecycle Sporogonous Cycle: Mosquito Stages Gametocytes P. falciparum P. vivax P. ovale P. malariae Human Liver Stages Exo-erythrocytic (hepatic) Cycle: Human Blood Stages Erythrocytic Cycle:
    11. 11. Pathology <ul><li>Anemia: </li></ul><ul><ul><li>P. Vivax - retiform RBC </li></ul></ul><ul><ul><li>P. Malariae - mature RBC </li></ul></ul><ul><ul><li>P. Falciparum - every RBC </li></ul></ul><ul><li>Prolifeation of mononuclear phagocyte </li></ul><ul><ul><li>hepatomegaly </li></ul></ul><ul><ul><li>splenomegaly </li></ul></ul><ul><li>Cerebral edema & congestion </li></ul>
    12. 12. Symptoms of Malaria <ul><li>Fever is by far the most common symptom, but is by no means the only one </li></ul><ul><li>Often can have constellation of symptoms described as “flu-like” </li></ul><ul><li>Other symptoms can include: chills, fatigue, weakness, headache, nausea, vomiting, diarrhea, muscle aches, mental status changes </li></ul>
    13. 13. Clinical manifestation <ul><li>Incubation period: </li></ul><ul><li>quartan malaria: 24-30 day </li></ul><ul><li>tertian malaria: 13~15 day </li></ul><ul><li>malignant malaria: 7~12 day </li></ul>
    14. 14. Clinical manifestation <ul><li>Typical attack </li></ul><ul><ul><li>Chill: abrupt onset, shivering, pale face,cyanosis. Last 10 min or 1~2hr. </li></ul></ul><ul><ul><li>High fever: T rise to 40 o C with malaise, myalgia, thirsty. Last 2~6 Hr. </li></ul></ul><ul><ul><li>Sweating: profuse sweating with restlessness </li></ul></ul><ul><ul><li>regular 48 hr. or 72 hr. Cycle </li></ul></ul>
    15. 15. Clinical manifestation <ul><li>Signs </li></ul><ul><ul><li>anemia </li></ul></ul><ul><ul><li>splenomegaly </li></ul></ul><ul><ul><li>hepatomegaly, ALT elevate </li></ul></ul>
    16. 16. Clinical manifestation <ul><li>Perniciouse attack: cause by P. Falciparum </li></ul><ul><ul><li>cerebral malaria </li></ul></ul><ul><ul><ul><li>high fever, headache, vomiting, convulsion delirum, respiratory failure </li></ul></ul></ul><ul><ul><li>hyperpyrexia type </li></ul></ul><ul><ul><li>T> 42 0 C, convulsion, delirium </li></ul></ul><ul><ul><li>Relapse: early relapse - <3m, </li></ul></ul><ul><ul><li>later relapse - >6m </li></ul></ul>
    17. 17. Clinical manifestation <ul><li>Malaria caused by transfusion </li></ul><ul><ul><ul><li>incubation period: 7~10 day </li></ul></ul></ul><ul><ul><ul><li>no exerythrogenic phase, no relapse </li></ul></ul></ul>
    18. 21. Complications <ul><li>Black- water- fever: </li></ul><ul><ul><li>cause: 1/inadequate G-6-PD </li></ul></ul><ul><ul><li>2/The toxin release by malarial parasite </li></ul></ul><ul><ul><li>3/Allergic reaction to anti-malarial drugs </li></ul></ul><ul><ul><li>feature:1/chill & fever </li></ul></ul><ul><ul><li>2/dark red or black urine </li></ul></ul><ul><ul><li>3/severe hemolytic anemia </li></ul></ul><ul><li>Acute glomerulonephritis </li></ul>
    19. 22. Malaria Mortality <ul><li>2 main ways it kills: </li></ul><ul><li>Anemia </li></ul><ul><ul><li>Parasites destroy red blood cells </li></ul></ul><ul><ul><li>Associated with increased mortality </li></ul></ul><ul><li>Cerebral malaria </li></ul><ul><ul><li>Damages brain and other vital organs </li></ul></ul><ul><ul><li>Fatality rate of 15% or more </li></ul></ul>
    20. 23. Laboratory Findings <ul><li>Blood picture: decrease in RBC & Hb </li></ul><ul><li>blood film for parasite </li></ul><ul><li>serological examination </li></ul><ul><ul><li>ELISA for P. antigen </li></ul></ul><ul><ul><li>DNA hybridization </li></ul></ul>
    21. 26. Plasmodium vivax Ring stage Gametocyte Trophozoite Schizont
    22. 27. Plasmodium malariae Ring stage Gametocyte Trophozoite Schizont
    23. 28. Plasmodium ovale Ring Trophozoite Schizont Gametocyte
    24. 46. Diagnosis <ul><li>Epidemiological data </li></ul><ul><ul><li>endemic zone </li></ul></ul><ul><ul><li>blood transfusion </li></ul></ul><ul><li>Clinical manifestation </li></ul><ul><li>Laboratory findings </li></ul><ul><li>Diagnostic treatment: </li></ul><ul><ul><li>chloroqunine for 3 days </li></ul></ul>
    25. 47. Differential Diagnosis <ul><li>Typhoid fever </li></ul><ul><li>Septicemia </li></ul><ul><li>Leptospirosis </li></ul><ul><li>Encephalitis B </li></ul>
    26. 49. Roll Back Malaria (RBM) <ul><li>Founded by: </li></ul><ul><li>World Health Organization (WHO), </li></ul><ul><li>United Nations Development Program (UNDP), </li></ul><ul><li>United Nations Children's Fund (UNICEF) </li></ul><ul><li>and World Bank </li></ul><ul><li>Includes national governments, civil society and non-governmental organizations, etc. </li></ul><ul><li>Provides framework for coordination between Ministries of Health and various organizations </li></ul>
    27. 50. Roll Back Malaria (RBM) <ul><li>The goal of Roll Back Malaria, established as a health initiative by WHO and its partners in 1998, is to halve the world's malaria burden by 2010. </li></ul><ul><li>At the Africa Summit on RBM, April 2000, Heads of State or senior representatives from 44 malaria-afflicted countries in Africa agreed to a series of interim goals to be attained by 2005. </li></ul><ul><li>Global program with clear strategies </li></ul><ul><li>Provides framework for Action </li></ul><ul><li>Touts prevention and treatment </li></ul>
    28. 51. Roll Back Malaria (RBM) Goals - At least 60% <ul><li>At least 60% of those with malaria should be able to access and use correct, affordable and appropriate treatment within 24 hours. </li></ul><ul><li>At least 60% of those at risk of malaria, particularly children under five years of age and pregnant women should use insecticide treated mosquito nets. </li></ul><ul><li>At least 60% of pregnant women at risk of malaria should have access to chemoprophylaxis or intermittent presumptive treatment. </li></ul>
    29. 52. Treatment <ul><li>Anti-malarial drugs </li></ul><ul><li>Chloroquine-susceptable infection </li></ul><ul><ul><li>chloroquine : 1g /d, for 3 day, p.o. </li></ul></ul><ul><ul><li>primaquine: for 8day, p.o. </li></ul></ul><ul><li>Chloroquine-resistant infection </li></ul><ul><ul><li>mefloguine: </li></ul></ul><ul><ul><li>artemisinine </li></ul></ul>
    30. 53. Treatment <ul><li>Pernicious attack </li></ul><ul><ul><li>Chloroquine: 10mg/kg iv drop in 4 hr. Then 5mg/kg, iv drop in 2 hr. </li></ul></ul><ul><ul><li>Quinine: 500mg iv drop in 4 hr. </li></ul></ul><ul><li>Radical therapy </li></ul><ul><li>Chloroquine (3 day) + primaquine ( 8 day ) </li></ul>
    31. 54. Countries with at least one study indicating chloroquine total failure rate > 10 % No failure reported Chloroquine total failure rate < 10% No recent data available P- falciparum resistance to chloroquine Source: WHO global database on drug resistance 1996-2004
    32. 55. P. falciparum resistance to sulfadoxine/pyrimethamine Source: WHO global database on drug resistance 1996-2004 Countries with at least one study indicating pyrimethamine-sulfadoxine total failure rate > 10% No failure reported P yrimethamine-sulfadoxine total failure rate < 10% No recent data available
    33. 56. P. falciparum resistance to mefloquine Source: WHO global database on drug resistance 1996-2004 Countries with at least one study indicating mefloquine total failure rate > 20% No failure reported Mefloquine total failure rate < 10% No recent data available Countries with at least one study indicating mefloquine total failure rate > 10%
    34. 57. P.vivax malaria distribution and Reported Treatment or Prophylaxis Failures or True Resistance, 2004 Source: WHO RBM Department, 2004 Vivax resistance to CQ confirmed in Guyana, Indonesia and Peru
    35. 58. Rationale for antimalarial combination therapy <ul><li>Advantages of combining two or more antimalarial drugs: </li></ul><ul><ul><li>First cure rates are usually increased. </li></ul></ul><ul><ul><li>Second, in the rare event that a mutant parasite which is resistant to one of the drugs arises de-novo during the course of the infection, it will be killed by the other drug. This mutual protection prevents the emergence of resistance. </li></ul></ul><ul><li>Both partner drugs in a combination must be independently effective. </li></ul><ul><li>Risks: Increased costs and increased side effects </li></ul>
    36. 59. The choice of artemisinin combination therapy (ACT) <ul><li>There are now more trials involving artemisinin and its derivatives than other antimalarial drugs, so although there are still gaps in our knowledge, there is a reasonable evidence base on safety and efficacy from which to base recommendations. </li></ul>Combinations which have been evaluated: piperaquine artemisinin + mefloquine artesunate + piperaquine dihydroartemisinin + mefloquine lumefantrine artemether + mefloquine naphthoquine chloroquine amodiaquine sulfadoxine-pyrimaethaminine mefloquine proguanil-dapsone chlorproguanil-dapsone atovaquone-proguanil clindamycin tetracycline doxycycline
    37. 60. Response to increasing resistance Combination therapies recommended by WHO <ul><li>Artesunate + amodiaquine </li></ul><ul><li>Artemether/lumefantrine </li></ul><ul><li>Artesunate + SP </li></ul><ul><li>Artesunate + mefloquine </li></ul>WHO Technical Consultation on “ Antimalarial Combination Therapy” – April 2001 ACTs FDC
    38. 61. Prevention <ul><li>Drug prophylaxis </li></ul><ul><ul><li>chloroquine: 0.3g once a week </li></ul></ul><ul><ul><li>doxycycline </li></ul></ul><ul><li>Kill mosquito </li></ul><ul><li>Vaccination </li></ul>
    39. 68. <ul><li>TOGETHER WE CAN BEAT MALARIA </li></ul><ul><li>THANK YOU FOR LISTENING </li></ul>