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 Malaria occurs in about 100 countries worldwide 40% of the global population is at risk of malaria 40% of the global population is at risk of malaria Over 300 million acute cases annually Over 300 million acute cases annually At least one million deaths annually At least one million deaths annually Malaria kills an African child every 30 seconds 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 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

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

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

Clinical Features Indefinite malaise, anemia, splenomegaly and slowly rising fever of several days duration 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 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 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 The above features may progress to jaundice, coagulation defects, shock, renal and hepatic failure, acute encephalopathy, pulmonary and cerebral oedema, coma and death

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

Poor prognostic factors Clinical: Agitation,hyperventilation, hypothermia,bleeding,deep coma,cunvulsions, anuria and shock. Clinical: Agitation,hyperventilation, hypothermia,bleeding,deep coma,cunvulsions, anuria and shock. Laboratory: Hypoglycemia( 3 mg%, SBR > 3mg%, ALT>3XULN, TLC >12000/cmm, PCV 3sec. Laboratory: Hypoglycemia( 3 mg%, SBR > 3mg%, ALT>3XULN, TLC >12000/cmm, PCV 3sec. Parasitology: Inceased mortality at >100,000/µl(approx: 2%), High mortality at >500,000/µl, >5% of Neutrophils with pigment. Parasitology: Inceased mortality at >100,000/µl(approx: 2%), High mortality at >500,000/µl, >5% of Neutrophils with pigment.

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

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

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.

Diagnostic points 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 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 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.

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 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 Resistance in vivo has been reported to all antimalarial drugs except artemisnin and its derivatives

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

Established Resistance Chloroquine Chloroquine (amodiaquine, mefloquine, halofantrine, and quinine) Antifolate combination drugs Antifolate combination drugs (Sulphadoxine + Pyrimethamine) (Sulphadoxine + Pyrimethamine) Atovaquone Atovaquone

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

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

Artemisinin compounds Dihydroartemisinin Dihydroartemisinin Arteether Arteether Artesunate Artesunate Artemether Artemether

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

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

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

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

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 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 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) 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)

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) 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 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

Antibiotics Tetracycline and derivatives such as doxycycline are very potent antimalarials and are used for both treatment and prophylaxis 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 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 Parasitological response is slow to clindamycin and recrudescence rates are high

Chloroquine resistance As the malaria parasite digests haemoglobin, large amounts of a toxic by-product are formed 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) 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 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 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 It is unclear whether parasite resistance to other quino-line antimalarials occurs via similar mechanisms