2..malaria 2007


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2..malaria 2007

  1. 1. Blood Protozoa: Plasmodia
  2. 2. The plasmodia are sporozoa in which the sexual and asexual cycles of reproduction are completed in different host species. The sexual phase occurs within the gut of the female anopheles mosquito. The sexual cycle is called Sporogony, as it results in the generation of sporozoites. The asexual cycle occurs in humans and is called Schizogony, as it results in the formation of Schizonts.
  3. 3. The life cycle of plasmodia begins with the release of sporozoites from the saliva of the infecting mosquito into the blood stream. These released sporozoites circulate in the subcutaneous capillaries and circulate in the peripheral blood. Within 30 minutes or an hour, they attach to and invade the hepatocytes, a process believed to be mediated by a ligand present in the sporozoite outer protein coat.
  4. 4. After attachment, the merozoite invaginates the cell membrane and is slowly endocytosed. The intracellular parasite initially occurs as a ring shaped trophozoite, which emlarges and becomes more active and irregular in outline. Within a few hours, nuclear division occurs producing the multi-nucleated schizont. Cytoplasm condenses around each nucleus of the schizont to form a cluster of 6-24 merozoite daughter cells. About 48-72 hours after the initial invasion the infected erythrocytes rupture releasing the merozoites and producing the first clinical manifestations of the disease.
  5. 5. The newly released daughter cells invade other RBC’s, where most repeat the asexual cycle. Fever, the hallmark of malaria appears to be initiated with the release of merozoites. It is believed that the parasite-derived pyrogens may be the reason. Alternatively, fever may result from the release of interleukin-1 and/or TNF from the macrophages involved in the ingestion of the parasite or erythrocytic debris. Early in malaria, RBS’s appear to be infected at several different stages of the development of the parasite, as each induces sporulation at different times. The resulting fever, thus is irregular and hectic, that may reach 40-41.7 degree centigrade. This kind of temperature destroys mature parasites and ultimately a single population emerges, sporulation is synchronized and fever occurs in distinct paroxysms at 48 or 72 hours intervals.
  6. 6. Other daughter cells that do not invade RBC’s are transformed into sexual forms or gametocytes that differentiate into female microgamete and male macrogametes. These do not lyse RBC’s and continue to circulate in the peripheral blood until ingested by the mosquito. Sporogony, or the sexual cycle begins in the gut of the mosquito, when the gametocytes mature and effect fertilization. The resulting zygote penetrates the gut wall and vacuolates to form an oocyst where thousands of sporozoites are formed. The enlarging cyst finally ruptures, releasing the sporozoites into the body cavity of the mosquito which then penetrates the salivary glands rendering the mosquito infectious at the next bite.
  7. 7.  Pathogenesis and clinical findings:  All the pathological findings of malaria result from the destruction of RBC’s.  The incubation period between the bite of the mosquito and onset of disease is approximately 2 weeks.  The clinical manifestations vary with the species of plasmodia but typically include chills, fever, splenomegaly and anemia.  Anemia manifests due to the parasitized erythrocytes engulfed by the stimulated reticuloendothelial system or are destroyed at the time of sporulation.  Depression of marrow function,sequestration of erythrocytes within the enlarging spleen, and accelerated clearance of non-parasitized cells all appear to contribute to anemia (mechanism unclear).  The enlarged spleen characteristic of malaria is due to the congestion of the sinusoids with erythrocytes coupled with hyperplasia of lympohocytes and macrophages.
  8. 8.  Infection with P.falciparum is far more severe and it is characterized by infection of far more red cells than other plasmodia spp.  Untreated P.falciparum infection, results in the blocking of capillaries with the aggregates of parasitized red cells. This may lead to intravascular hemolysis, which when massive results in hemoglobinuria resulting in dark urine and hence the name blackwater fever. Hemoglobinuria can also lead to acute renal failure.  The blocking of capillaries impair the microcirculation and precipitate tissue hypoxia, lactic acidosis and hypoglycemia. Although deep tissues are involved, the brain is the most commonly affected. This manifests in cerebral malaria. The patient may develop delerium, convulsions, paralysis,, coma and rapid death, usually within 3 days.  Acute pulmonary insufficiency frequently accompanies cerebral malaria and may be the leading cause of death in such cases.
  9. 9.  Thrombocytopenia is common in malaria and may be related to both splenic pooling and a shortened platelet life span.  Involvement of visceral capillaries may result in vomiting, abdominal pain and diarrhea with or without bloody stools  The clinical findings include the malarial paroxysm.  This begins with a cold stage, which persists for 20-60 minutes. The patient experiences continous rigours and feels cold.  With the consequent increase in the body temperature, vasodilation commences, ushering in a hot stage. The temperature may rise a maximum of 104-107 degrees farenheit before it begins to fall.  The wet stage consists of a decrease in fever and profuse sweating. It leaves the patient exhausted, otherwise well, till the next onset of paroxysm.
  10. 10. Typical paroxysms first appear in the second or third week of fever, when the parasite sporulation becomes synchronized. In falciparum malaria, the synchronization may never take place and the fever remains hectic and unpredictable. Other symptoms include headache, myalgias and arthralgias.
  11. 11. A quick species and strain specific immunity is possible due to the high levels of antibodies developed that typically limits the parasite multiplication and moderates the clinical manifestations of the disease known as Premunition, with eventual recovery. Individuals with sickle-cell trait are protected as their RBC’s appear to have too little ATPase activity and cannot produce sufficient energy to support the growth of the parasite. Individuals homozygous recessive for duffy antigen. Individuals with G6PD deficiency .
  12. 12. Laboratory diagnosis involves the microscopic examination of peripheral blood stained with Giemsa’s stain.. Thick smears for presence of parasites. Thin smear for species identification. The appearance of each of the 4 species is sufficiently different for identification on which the treatment may differ.
  13. 13.  The parasitized erythrocyte in vivax and ovale infection is pale, enlarged and contains numerous red nuclear chromatin, known as Shuffner’s dots. All asexual stages (trophozoite, schizont, merozoite) may be seen simultaneously.  Ovale infected cells are elongated, frequently irregular and fimbriated in appearance.  Maliariae infected cells are not enlarged and do not contain granules. The trophozoites are seen as band forms and the merozoites are arranged in rossettes around a clump of central brownish-black malarial pigment or hemozoin, a hemoglobin degradation product.  The trophozoites of falciparum have small rings with the infected cells often showing more than one parasite lying against the margins of the cell. Intracytoplasmic granules known as Maurer’s dots may be present, fewer in number than the Schuffner’s dots.  Schizonts and merozoites are not present in the peripheral blood.  Gametocytes of falciparum are large and sausage or banana or crescent shaped. Other plasmodia gametocytes are spherical.  If more than 5% of red cells are parasitized is indicative of falciparum.
  14. 14. An ELISA test detects a protein HPR2, specific for falciparum. PCR based test for plasmodium nucleic acids are also available. Another rapid test “Optimal” to detect parasite lactate dehydrogenase is available and is able to distinguish between falciparum and vivax.
  15. 15. Treatment and Prevention: Chloroquine is the drug of choice for acute malaria.It kills the merozoites. P.falciparum strains resistant to chloroquine are increasing. Chloroqine also does not affect the hypnozoites of vivax and ovale in the liver (cause of relapses). Primaquine effective against the hypnozoites, but can induce severe hemolysis in G6PD deficient individuals. Hence, individuals should be tested for G6PD deficiency before administering primaquine.
  16. 16. Chloroquine and Mefloquine(schizonticidal agent) resistant strains of falciparum treated with Malarone (combination of atovaquone and proguanil). In severe falciparum cases, intravenous quinidine or quinine along with another anti-malarial such as Doxycycline or Clindamycin can be used.Artemisinins like artesunate or artemether are inexpensive with fewer side effects. Resistance to artesunate emerging from falciparum . Artemether and Lumefantrine in combination can be useful in such cases.
  17. 17. Prevention includes chemoprophylaxis of doxycycline or mefloquine or Malarone for travellers to chloroquine resistant falciparum endemic places. For other plasmodia, chloroquine starting 2 weeks before arrival and 6 weeks after departure from endemic places. Followed by 2 week course of primaquine to kill hypnozoites. Mosquito nets, repellents etc… useful. DDT and other insecticide sprays not effective any more. Drainage of stagnant water pools effective to prevent breeding of mosquitoes. No vaccine yet.