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Emerging Trends in Malaria

Emerging Trends in Malaria. By Professor Dr Intekhab Alam Department of medicine Postgraduate medical institute Lady Reading Hospital Peshawar. Disease Incidence & Trends. Malaria occurs in about 100 countries worldwide 40% of the global population is at risk of malaria

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Emerging Trends in Malaria

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  1. Emerging Trends in Malaria By Professor DrIntekhabAlam Department of medicine Postgraduate medical institute Lady Reading Hospital Peshawar

  2. Disease Incidence & Trends • Malaria occurs in about 100 countries worldwide • 40% of the global population is at risk of malaria • Over 300 million acute cases annually • At least one million deaths annually • Malaria kills an African child every 30 seconds • In Africa P. falciparum infection during pregnancy is estimated to cause as many as 10,000 maternal deaths each year Ref: World malaria situation; rbm.who.int/cmc/015/372/RBMinfosheet

  3. Prevalence-EMRO • Countries with moderate endemicity (Pakistan, Iraq, Iran and Saudi Arabia) • Countries with severe malaria problem (Afghanistan, Djibouti, Somalia, Sudan, and Yemen)

  4. Situation in Pakistan Epidemiology • Malaria belongs to the Oriental eco-epidemiological type • P. falciparum and P. Vivax are major species • In the 1990s, the annual number of cases oscillated between 74-112,000 of which about 40% were due to P. Falciparum • Due to poor reporting system less than 20% of the actual number of cases are recorded Constraint • Massive importation from Afghanistan • Resistance of P. falciparum to choloroquine and vector resistance to insecticides

  5. Clinical Features • Indefinite malaise, anemia, splenomegaly and slowly rising fever of several days duration • Followed by shaking chills and rapidly rising temperature, that ends with profuse sweating • Falciparum malaria (malignant tertian) may present a varied clinical picture with an atypical onset including diarrhoea • The above features may progress to jaundice, coagulation defects, shock, renal and hepatic failure, acute encephalopathy, pulmonary and cerebral oedema, coma and death

  6. Cerebral malaria Renal Failure Gastrointestinal type Shock type(Algid malaria. Severe liver damage Severe anemia (PCV < 15%) Hemolytic anemia (Black water fever). Acidosis. ARDS Hypoglycemia 2nd or 3rd trimester of pregnancy DIC Hyperparasitaemia (>5% nonimmune >20% in any) Complicated malaria

  7. Poor prognostic factors • Clinical:Agitation,hyperventilation, hypothermia,bleeding,deep coma,cunvulsions, anuria and shock. • Laboratory:Hypoglycemia(<40mg%), Acidosis(pH <7.3 or HCO3 <15mmol/l), S. Creat >3 mg%, SBR > 3mg%, ALT>3XULN, TLC >12000/cmm, PCV <15%, PLT < 50,000/cmm, PT >3sec. • Parasitology:Inceased mortality at >100,000/µl(approx: 2%), High mortality at >500,000/µl, >5% of Neutrophils with pigment.

  8. Diagnosis • Clinical (presumptive) diagnosis • Microscopy: Thick film(sensitivity 0.0001%.) Thin film (sensitivity 0.05%) • Antigen detection tests: rapid and sensitive (0.0001%.). PfHRP2 dipstick or Plasmodium LDH dipstick tests. • Molecular tests: e.g. PCR

  9. Morphological characteristics of the four species Simple light microscopic examination of Giemsa stained blood films is the most widely practiced and useful method for definitive malaria diagnosis

  10. Diagnostic points • Rings appear fine and Red Cells are not enlarged.  • delicate and there may be several in one cell. • Some rings may have two chromatin dots.  • Presence of marginal forms.  • It is unusual to see developing forms in peripheral blood films.  • Gametocytes have a characteristic crescent shape appearance.  However, they do not usually appear in the blood for the first four weeks of infection.  • Maurer's dots may be present.

  11. Red cells containing parasites are usually enlarged.  Schuffner's dots are frequently present in the red cells as shown above.  The mature ring forms tend to be large and coarse. Developing forms are frequently present. Diagnostic points

  12. Ring forms may have a squarish appearance. Band forms are a characteristic of this species.  Mature schizonts may have a typical daisy head appearance with up to ten merozoites. Red cells are not enlarged. Chromatin dot may be on the inner surface of the ring. Diagnostic points

  13. Red cells enlarged. Comet forms common (top right) Rings large and coarse. Schuffner's dots, when present, may be prominent. Mature schizonts similar to those of P.malariae but larger and more coarse. Diagnostic points

  14. Current status of drug-resistant malaria • Resistance to antimalarial drugs has been described for two of the four species of malaria parasite that naturally infect humans, P. falciparum and P. vivax • Resistance in vivo has been reported to all antimalarial drugs except artemisnin and its derivatives

  15. Mechanism of Resistance • Physiological adaptations due to non genetic changes • Selection of previously existing drug resistant cells from a mixed population under drug pressure • Spontaneous mutation • Mutation of extra-nuclear genes, or • The existence of plasmid-like factors

  16. EstablishedResistance • Chloroquine (amodiaquine, mefloquine, halofantrine, and quinine) • Antifolate combination drugs (Sulphadoxine + Pyrimethamine) • Atovaquone

  17. Drug Resistance • Declining trend in cure rates of previously effective antimalarial drugs reported over last 3 decades reflects development of resistant strains of Plasmodium

  18. Drugs Available for Treatment • Chlorquin phosphate. • Artemisinin and its derivatives • Quinine hydrochloride. • Antibiotics (Doxycycline and Clindamycine). • Mefloquin hydrochloride. • Malarone (Atovaquone+Proguanil). • Halofantrine. • Pyrimethamine+Sulfadoxine. • Pimaquine. • Proguanil.

  19. Artemisinin compounds • Dihydroartemisinin • Arteether • Artesunate • Artemether

  20. Dihydroartemisinin • Most rapidly acting antimalarial drug • Only artemisinin derivative available in active metabolite form • Fastest fever clearance time • Fastest parasite clearance time • Schizontocidal and Gametocidal effects • Fast relief of symptoms and reduces transmission • No resistance reported to date • Does not exhibit mutagenic or teratogenic effects • Well tolerated even at 987.5mg/kg dose • Easy dosage regime i.e. once daily

  21. Word of caution!!!! • Safety in pregnancy (Embryotoxic in animal studies). • High recrudescence rates (approx: 50%) • Preventionof future resistance to Artimisinin and its derivatives. (role of ACTs)

  22. Questions ???

  23. Thank You

  24. Miscellaneous compounds • Halofantrine produce potentially fatal cardiac conduction abnormalities (specifically, prolongation of the PR and QT interval), limiting its usefulness • Lumefantrine, a fluoro-methanol compound, is being produced as a fixed combination tablet with artemether

  25. Artemisinin compounds • Sesquiterpine lactone compounds • Synthesized from the plant Artemisia annua • Used for treatment of severe malaria • Shown very rapid parasite clearance times and faster fever resolution than with quinine

  26. Quinine and related compounds • Quinine, along with its dextroisomer quinidine, has been the drug of last resort for the treatment of malaria, especially severe disease • Amodiaquine is a relatively widely available compound closely related to chloroquine • Other quinine-related compounds in common use include primaquine (specifically used for eliminating the exoerythrocytic forms of P. vivax and P. ovale that cause relapses), and mefloquine (a quinoline-methanol derivative of quinine)

  27. Antifolate combination drugs • These drugs are various combinations of dihydrofolate-reductase inhibitors (proguanil, chlorproguanil, pyrimethamine, and trimethoprim) and sulfa drugs (dapsone, sulfalene, sulfamethoxazole, sulfadoxine, and others) • A new combination of chlorproguanil and dapsone, also known as Lap-Dap, has a much more potent synergistic effect on malaria than existing drugs such as SP

  28. Antibiotics • Tetracycline and derivatives such as doxycycline are very potent antimalarials and are used for both treatment and prophylaxis • Clindamycin has been used but offers only limited advantage when compared to other available anti-malarial drugs • Parasitological response is slow to clindamycin and recrudescence rates are high

  29. Chloroquine resistance • As the malaria parasite digests haemoglobin, large amounts of a toxic by-product are formed • The parasite polymerizes this by-product in its food vacuole, producing non-toxic haemozoin (malaria pigment) • It is believed that resistance of P. falciparum to chloroquine is related to an increased capacity for the parasite to expel chloroquine at a rate that does not allow chloroquine to reach levels required for inhibition of haem polymerization • Chloroquine resistance can be reversed by drugs which interfere with this efflux system • It is unclear whether parasite resistance to other quino-line antimalarials occurs via similar mechanisms

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